eml opioids for cancer pain: a comparative … · pain is a frequent and impacting symptom not only...

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EML OPIOIDS FOR CANCER PAIN: A COMPARATIVE OVERVIEW

General Index

Author’s Information 3

INTRODUCTION 4

CANCER PAIN 6 Definition 6

References 7

CANCER PAIN 8 Prevalence 8

References 10 Pathophysiology 12

References 13

Treatment of Cancer Pain 14 References 16

METHADONE 17 Introduction 17 Pharmacology of methadone 17

Chemical characteristics 17 Pharmacodynamics 17 Pharmacokinetics 18 Drug interactions 19 References 22

Efficacy of Methadone in Clinical Studies 24 Figure 1. Consort – like report of Eligible Papers. 25 Summary of data for Efficacy (Table 1, Appendix 1). 26 Search Method 26 Systematic Review (Table 3, Appendix 1). 28 Retrospective Studies (Table 4, Appendix 1). 30 Prospective Open Label studies; Observational studies (Table 5, Appendix 1). 31 Case Report; Case Series (Table 6, Appendix 1). 32 References 33

Toxicities of Methadone in Clinical Studies 37 Figure 1. Search for Toxicity. 37 Summary of data for Toxicity (Table 1, Appendix 2). 38 Search Method 38 Review (Table 2, Appendix 2). 39 Retrospective Studies (Table 3, Appendix 2). 40 Observational Studies (Table 4, Appendix 2). 41 Case Reports/Case Series (Table 5, Appendix 2). 42 References 43 Clinical considerations on Methadone 44 References 45

TRANSDERMAL FENTANYL SYSTEM (TTS) 47 Introduction 47 Pharmacokinetics and Pharmacodynamics 47

References 49 Efficacy of Transdermal Fentanyl in clinical Studies. 51

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Figure 1. Consort – like report of Eligible Papers for Efficacy. 51 Summary of data for Efficacy (Table 1, Appendix 2). 51 Randomized Trial (Table 2, Appendix 3). 52 Retrospective Studies (Table 3, Appendix 3). 53 Prospective Open-label Studies; Observational Studies (Table 4, Appendix 3). 55 Systematic Reviews and Non-Systematic reviews (Table 5, Appendix 3). 56 References 58

Toxicity of Transdermal Fentanyl in Clinical Studies. 61 Figure 2. Consort – like report of Eligible Papers for Toxicity. 61 Summary of data for Toxicity (Table 1, Appendix 4). 62 Observational Studies (Table 2, Appendix 4). 62 Case Report; Case Series (Table 3, Appendix 4). 63 References 64 Clinical considerations on Transdermal Fentanyl 65 References 67

TRAMADOL 69 Introduction 69

References 71 Efficacy of Tramadol in Clinical Studies 72

Figure 1. Consort-Like diagram of selected papers for efficacy. 72 Summary of data for Efficacy (Table 1, Appendix 5). 73 Randomized Controlled Trials (Table 2, Appendix 5). 74 Systematic Review (Table 3, Appendix 5). 75 Prospective Open Label Study (Table 4, Appendix 5). 76 References 77

Toxicity of Tramadol in clinical studies. 78 Figure 1. Consort-Like diagram of selected papers for Toxicities. 78 Case Report; Case Series (Table 1, Appendix 6). 79 References 80 Adverse effects of tramadol 81 References 82 Clinical Role of Tramadol 83 References 84

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Author’s Information

Carla Ida Ripamonti M.D.

Head, Supportive Care in Cancer Unit,

Department of Hematology and Pediatric Onco-Hematology

Fondazione IRCCS, Istituto Nazionale Tumori

Via Venezian, 1 20133 Milano, Italy

Email: [email protected]

Tel. (+39) 02 23903644

Fax (+39) 02 23904847

Network Italiano Cure di Supporto in Oncologia (NICSO) www.nicsonet.it

Raffaele Giusti M.D.

Medical Oncology Unit Sant’Andrea Hospital of Rome;

Via di Grottarossa 1035-39, 00189 Rome – Italy.

Phone number: (+39) 0633775800 (Institutional)

Fax number (+39) 063776346

E-mail address: [email protected]; [email protected]

Network Italiano Cure di Supporto in Oncologia (NICSO) www.nicsonet.it

mailto:[email protected]

http://www.nicsonet.it/

mailto:[email protected]

http://www.nicsonet.it/

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INTRODUCTION

Cancer pain is commonly treated effectively with opioids administered at regular intervals with

rescue doses for the management of episodic pain.

Opioids are the cornerstone of cancer pain management and their use has been increasing in the last

years all over the world. Today, opioid therapy represents the best choice to control pain for the

majority of cancer patients.

Pain management must be individualized taking into account the available drugs, patient's clinical

situation and intensity of pain so nowadays more analgesic drugs must be made available.

Morphine is the strong opioid of choice for the treatment of moderate to severe cancer pain

according to the World Health Organization. This recommendation from the WHO was derived by

virtue of availability, familiarity to clinicians, established effectiveness, and simplicity of

administration with relative inexpensive cost. It was not based on proven therapeutic superiority

over other options.

In clinical practice, patients treated with oral morphine sometimes present with the following

clinical situations: (1) pain is controlled but the patient experiences some intolerable adverse

effects; (2) pain is not adequately controlled and it is impossible to increase the morphine dose

because of adverse effects; (3) pain is not adequately controlled by continuously increasing the dose

of morphine but the morphine does not produce adverse effects. However, there is no single opioid

of choice for all patients, but one opioid can be optimal for an individual patient.

Methadone is another attractive alternative mu-opioid analgesic because of its lack of neuroactive

metabolites, clearance independent of renal function, good oral bioavailability, extremely low cost,

long half-life with fewer doses needed per day, potential to control pain no longer responsive to

other opioids, and other extra-opioid analgesic effects caused by its noncompetitive antagonist

activity at the N-methyl-D-aspartate receptors. Moreover methadone presents low tolerance with

the advantage to avoid a continuous increase of the dose.

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In special situations, patient may experience several comorbidities such as malabsorption, vomiting

or severe constipation resulting in not taking oral agents so alternative routes like the transdermal

one are strongly recommended. The same route is indicated also in patients with poor compliance to

medications and in patients who are already taking a large number of drugs.

In these cases, transdermal fentanyl may represent the best way to cancer pain management. Due to

its pharmacokinetic characteristics, it also represents a mainstay of treatment for patients with renal

failure for which the assumption of morphine, codeine, tramadol and all analgesic drugs which have

active metabolites being excreted renally are not recommended.

As physicians cannot predict a patients’ treatment response, previous opioid exposure can be

considered as a therapeutic trial that allows the determination of the individual response. After

starting the prescribed initial opioid, clinical efficacy may decrease gradually in time or even

abruptly, resulting in a need for dose increase. In some cases dose increases do not provide

analgesia, and further dose increments are ineffective. Alternatively, adverse effects may occur that

are difficult to control with symptomatic therapies.

If an opioid fails to provide adequate analgesia or causes unmanageable adverse effects, this agent

has to be stopped and a different opioid should be offered.

For these reason, we strongly support the introduction of methadone, fentanyl and tramadol into the

new World Health Organization list of essential medicines for the management of cancer pain.

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CANCER PAIN

Definition

According to the International Association for the Study of Pain (IASP), Pain is “an unpleasant

sensory and emotional experience associated with actual or potential tissue damage or described in

terms of such damage” (1,2). Pain is both a sensation (conscious awareness of a noxious stimulus)

and an emotional experience (intense feelings of displeasure resulting in a set of reactive behavior).

Pain is always a subjective sensation; it is what the patient says hurts (1,2) and may be affected by

emotional (anxiety, depression, hopelessness), social and spiritual components (3) thus defined

"Total pain".

The perception of the intensity of pain is not proportional to the type or to the extension of the

tissue damage bur depends on the interactions between nociceptive and non-nociceptive impulses in

ascending pathways, in relation to the activation of descending pain-inhibitory systems.

Pain has been defined as the fifth vital sign by the American Pain Society and its routine

assessment is emphasizes by international guidelines.

A proper pain assessment is fundamental for an effective and individualized treatment. Poor pain

assessment is the greatest barrier to effective cancer pain management (4). As pain is a subjective

perception, objective measurement is not possible. A variety of instruments have been developed to

measure the intensity of pain (5).

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References

1. IASP Subcommittee on Taxonomy. Pain terms: a list with definitions and notes on usage. Pain

1979; 6: 249-252

2. International Association for the Study of Pain. Subcommittee on Taxonomy. Classification of

chronic pain. Descriptors of chronic pain syndromes and definition of pain terms. Pain (Suppl 3),

S1-S225, 1986

3.Quill Timothy E. Caring for patients at the end of life. Oxford University Press. Oxford 2001

4. Von Roenn JH, Cleeland CS, Gonin R, Hatfield AK, Pandya KJ. Physician attitudes and practice

in cancer pain management. A survey from the Eastern Cooperative Oncology Group. Ann Intern

Med 1993;119:121-126

5. Caraceni A, Cherny N, Fainsinger R, et al. Pain measurement tools and methods in clinical

research in palliative care: recommendations of an Expert Working Group of the European

Association of Palliative Care. J Pain Symptom Manage 2002;23:239-255.

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CANCER PAIN

Prevalence

Pain is a frequent and impacting symptom not only in advanced cancer but also in any phase of the

disease. Pain occurs at diagnosis in 20% to 50 % of patients with cancer (1). Pain prevalence ranges

from 64% in patients with metastatic, advanced or terminal phase disease, 59% in patients on

anticancer treatment and 33% in patients after curative treatment (2).

These data show that, although several guidelines for the treatment of oncological pain have been

published (3-5), pain continues to be present in a high percentage of patients in any stage of the

disease. Furthermore, no difference in pain prevalence was found between patients on anticancer

active treatment and those with advanced or terminal disease. In the latter population, the most

frequent causes of pain are painful peripheral neuropathy, radiation-induced brachial plexopathy,

chronic pelvic pain secondary to radiation, and post-surgical pain (6). It is necessary to change the

oncological clinical practice by implementing a routine pain evaluation, with an analysis of its

causes and an appropriate use of analgesic drugs within a multimodal approach. Finally, we have to

consider the population of survivors, who need an organized follow up (7,8).

In the 18 studies that reported the pain severity, one third of the patients rated their pain as moderate

to severe (2); these patients require a therapy with opioid analgesics to be adequately treated. More

precisely, they need a personalized therapy with the right drug at the right dose through the most

appropriate route of administration. Opioid switching, the use of adjuvant drugs, and the change of

the route of administration must go hand in hand throughout the entire patient’s history, and have to

consider both the presence of side effects and the patient’s compliance.

The different pain prevalence according to the site of the primary tumour is well known and

described; certain types of cancer are characterized by a high percentage of patients, that is more

than 70%, that experience pain and these are head-and-neck, pancreatic, genitourinary, oesophagus,

and prostate cancer (2, 9).

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Moreover, nearly half of the cancer patients were under-treated with a high variability across study

designs and clinical settings. Recent studies conducted both in Italy and in Europe (10,11)

confirmed these data, showing that pain was present in all phases of cancer disease (early and

metastatic) and was not adequately treated in a significant percentage of patients, ranging from 56%

to 82.3%.

Age affects cancer pain (12): younger patients experience more pain and more pain flares than older

patients (13); moreover elderly patients receive less opioids than younger patients (14).

In prospective study (15) the adequacy of analgesic care of cancer patients was assessed by means

of Pain Management Index (PMI) in 1802 valid cases of in- and outpatients with

advanced/metastatic solid tumor enrolled in specifically devoted to cancer and/or pain management

(oncology/pain /palliative centers or hospices). The study showed that patients were still classified

as potentially under-treated in 25.3% of the cases (range 9.8%–55.3%) (15).

Although in the last years the percentage of patients undertreated is reduced of 25% (43.4% vs.

31.8%) (16) more than 1/3 of the cancer patients with pain do not receive an adequate treatment.

Contrary to the percentage of incidence of pain reported in hematologic patients (5% with leukemia

and 38% with lymphoma) in the past literature a significant proportion of patients with lymphoma

and leukemia may suffer from pain not only in the last months of life (83%)(10,17) but also at the

time of diagnosis and during active therapies (18).

According to the World Health Organization (WHO) the incidence of cancer was 12,667,470 new

cases in 2008 and based on the projections it will be more than15 million in 2020 (19).

These statistics suggest that cancer-related pain may be a major issue of healthcare systems

worldwide.

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References

1. Fischer DJ, Villines D, Kim YO, et al. Anxiety, depression, and pain: differences by primary

cancer. Supporti Care Cancer 2010; 18/7: 801-810

2. Van den Beuken-van Everdingen MHJ, De Rijke JM, Kessels AG et al. Prevalence of pain in

patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18: 1437–1449.

3. W.H.O. Cancer pain relief. 2nd

Edition. Geneva: World Health Organization 1996

4. Ripamonti CI, Santini D, Maranzano E, et al. ESMO Guidelines Working Group. Management

of Cancer Pain: ESMO Clinical Practice Guidelines. Ann Oncol 2012; 23 (Suppl 7):vii139-154

5. Caraceni A, Hanks G, Kaasa S, et al. European Palliative Care Research Collaboration

(EPCRC). European Association for Palliative Care (EAPC). Use of opioid analgesics in the

treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol

2012; 13:e58-68

6. Sun V, Borneman T, Piper B, Koczywas M, Ferrell B. Barriers to pain assessment and

management in cancer survivorship. J Cancer Surviv 2008; 2: 65-71

7. Glare PA, Davies PS, Finlay E, et al. Pain in cancer survivors. J Clin Oncol 2014 ; 32 :1739-

1747

8. Burton AW, Fanciullo GJ, Beasley RD, Fisch MJ. Chronic pain in cancer survivor: a new

frontier. Pain Med 2007; 8: 189-198

9. Higginson IJ and Murtagh F. Cancer pain epidemiology. In: Cancer Pain: assessment and

management (Bruera ED and Portenoy RK Editors). Cambridge University Press 2010; 3: 37-52

10. Costantini M, Ripamonti C, Beccaro M et al. Prevalence, distress, management and relief of

pain during the last three months of cancer patients’ life. Results of an Italian mortality follow-

back survey. Ann Oncol 2009; 20: 729–735.

11. Breivik H, Cherny N, Collett F et al. Cancer-related pain: a pan-European survey of prevalence,

treatment, and patient attitudes. Ann Oncol 2009; 20: 1420–1433

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12. Ripamonti CI, Sichetti DAP, Fanizza C, Tognoni EG, Romero M on the behalf of ECAD_O

Working Group. Is pain reporting to health care professionals age-related? A cross sectional

multicenter study in a hospital setting. Expert Opin. Pharmacother 2013; 14(15): 2011-2017

13. Green CR, Hart G, Johnson T. Cancer pain: an age-based analysis. Pain Med 2010; 11/10:

1525-1536

14. Cleary JF. The pharmacologic management of cancer pain. J Palliat Med 2007; 10/6: 1369-1394

15. Apolone G, Corli O, Caraceni A et al. Pattern and quality of care of cancer pain management.

Results from the Cancer Pain Outcome Research Study Group. Br J Cancer 2009; 100: 1566–

1574

16. Greco MT, Roberto A, Corli O, et al. Quality of cancer pain management: an update of a

systematic review of undertreatment of patients with cancer. J Clin Oncol 2014; 32:4149-4154

17. Bandieri E, Sichetti D, Luppi M, Di Biagio K, Ripamonti C, Tognoni G, Belfiglio M, Romero

M. Is pain in haematological malignancies under-recognised? The results from Italian ECAD-O

survey. Leukemia Research 2010 ;34: e334-e335

18. Morselli M, Bandieri E, Zanin R et al. Pain and emotional distress in leukemia patients at

diagnosis. Leukemia Research 2010 Feb;34(2):e67-8

19. Frankish H. 15 million new cancer cases per year by 2020, says WHO. The Lancet 2003; 361:

1278

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Pathophysiology

Pain can be caused by cancer itself or comorbidities; it may result following surgery, radiotherapy,

chemotherapy, targeted therapy, supportive care treatments, and/or diagnostic procedures; or it may

be unrelated to cancer (1).

Cancer pain may be acute, chronic or episodic. Episodic pain (breakthrough pain) may be

unpredictable or predictable (incident pain).

From a pathophysiological point of view, pain can be classified as nociceptive (somatic and

visceral), neuropathic (central, peripheral, sympathetic) idiopathic (2,3). However, in the clinical

setting, pain is more frequently a mixed pain and may involve multiple mechanisms, explaining the

utility of combinations of different classes of analgesic drugs.

About 80% of patients with cancer have ≥ 2 types of pain, and 33% have ≥ 4 types of pain. Pain

can be either acute or chronic with acute exacerbations; nociceptive, neuropathic, or mixed; it can

also be related to benign comorbidities (e.g. bedsores, osteoporosis, postoperative scar pain,

diabetic neuropathy). Different and concomitant causes of pain need a multimodal approach as far

as the evaluation of the causes, the intensity, and the treatment are concerned.

In cancer patients, pain is a direct result of the tumor in 75-80% of cases, is caused by anticancer

treatments in 15-19% of patients and is unrelated to cancer and its treatments in 3-5% (4). This

coincidental pain has a variety of causes, for example it may be related to debility, decubitus

(nociceptive), or post-herpetic neuralgia (neuropathic-peripheral and central). Pain may also be a

consequence of the diagnostic procedures used in cancer treatment (1). Numerous distinct acute and

chronic cancer pain syndromes have been recognized and described (4,5).

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References

1. Ripamonti CI, Bossi P, Santini D, Fallon M. Pain related to cancer treatments and diagnostic

procedures: a no man’s land? Ann Oncol 2014; 25:1097-1106

2. Patt RB. Classification of cancer pain and cancer pain syndromes. In: Patt RB, (Editor). Cancer

Pain. Philadelphia: J.B. Lippincott Company. 1993;3-22.

3. Fields HL, Rowbotham MC. Multiple mechanisms of neuropathic pain: a clinical perspective.

In: Gebhart GF, Hammond DL, Jensen TS, Editors. Proceedings of the 7th World Congress on

Pain: progress in pain research and management, Vol 2. Seattle, WA: Press. 1994;437-454.

4. Shaiova L, Farber LA, Aggarwal SK. Difficult Pain Syndromes: Neuropathic pain, bone pain,

and visceral pain . In: Berger AM, Shuster JL, Von Roenn JH. (Editors) Principles and Practice

of Palliative Care and Supportive Oncology. IV th EditionLippincott Williams & Wilkins 2013;

1: 2-21

5. Reddy SK. Causes and mechanisms of pain in palliative care patients. In: Bruera E, Higginson

IJ, Ripamonti C, von Gunten C, Editors. Textbook of Palliative Medicine. Great Britain:

Edward Arnold (Publishers) Ltd. 2006;367-379.

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Treatment of Cancer Pain

Despite published guidelines and educational programs on the assessment and treatment of cancer-

related pain, in any stage of oncological disease, unrelieved pain continues to be a substantial

worldwide public health concern either in patients with solid and hematological malignancies. The

proper and regular self-reporting assessment of pain is the first step for an effective and

individualized treatment. According to the W.H.O. guidelines, opioid analgesics are the mainstay of

analgesic therapy and are classified according to their ability to control mild to moderate pain (weak

opioids, second step of the W.H.O. analgesic ladder), and to control moderate to severe pain

(strong opioids , third step of the W.H.O. analgesic ladder). Opioid analgesics may be associated

with non-opioids drugs such as paracetamol or nonsteroidal anti-inflammatory drugs and to

adjuvant drugs (for neuropathic pain and symptom control). At the moment WHO guidelines are

under revision by experts.

In clinical practice the role and the utility of weak opioids (e.g. codeine, dihydrocodeine, tramadol)

is a controversial point (1,2) and further research on this topic is needed. Morphine has been placed

by WHO on its Essential Drug List since its inception in 1977.

Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in

the treatment of chronic cancer pain, but individual responses to these drugs can vary (3,4).

A study designed to compare the analgesic efficacy of four strong opioids, that are oral morphine,

oral oxycodone, transdermal fentanyl, and transdermal buprenorphine, show that the four drugs are

characterized by the same level of pain relief, but 8.9 to 14.4% of the patients are identified as not

responders (the highest percentage referring to patients treated with buprenorphine) and 11 to

15.3% of the patients as poor responders. Furthermore, even those patients who experience a good

analgesic response to these opioids need continuous dose adjustments (the highest increase being

needed by those patients treated with fentanyl) and patients treated with morphine frequently need

switches to other opioids. Patients treated with oxycodone more frequently need the use of adjuvant

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drugs. The side effects are similar, apart from those affecting the CNS, such as allucination and

confusion, which are more frequent during a treatment with morphine (3).

These data confirm that there is no evidence to show superiority or inferiority of these drugs

compared to morphine . The purpose of the overview is to highlight new data about the efficacy and

tolerability of opioids that are different than oral morphine, which is now the essential drug

according to WHO, [and alternatives limited to hydromorphone and oxycodone].

Among these new drugs we include methadone, transdermic fentanyl and tramadol.

Oral methadone is considered to be an useful and safe alternative to oral morphine. Because of its

pharmacokinetics and pharmacodynamics methadone is to be used by experts in order to avoid

overdose. Methadone has the potential to control pain which is difficulty controlled by other

opioids. Although the oral administration is considered the first choice, intravenous, subcutaneous,

rectal, transdermal, sublingual, intranasal, and spinal routes may be used in particular situations.

Transdermal opioids, such as fentanyl, are reserved to those patients whose opioid need is stable,

when gastrointestinal symptoms preclude the oral administration, and when compliance to oral

opioids (which need multiple daily administration) is poor.

Switching from one opioid to another can improve analgesia and tolerability (1).

Tramadol may be considered as an alternative to morphine in those countries where morphine is not

available.

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References

1. Ripamonti CI, Santini D, Maranzano E, Berti M and Roila F. Management of cancer pain:

ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;

23(Suppl. 7): vii139–vii154.

2. Bandieri E, Romero M, Ripamonti CI, Artioli F, Sichetti D, Fanizza C,. Randomized Trial of

Low-Dose Morphine Versus Weak Opioids in Moderate Cancer Pain. J Clin Oncol. 2016 Feb

10; 34(5): 436-42

3. Corli O, Floriani I, Roberto A, Montanari M, Galli F, Greco MT. Are strong opioids equally

effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV

“real life” trial on the variability of response to opioids. Ann Oncol 2016; 27:1107-1115

4. Caraceni A, Hanks G, Kaasa S, et al. European Palliative Care Research Collaboration

(EPCRC). European Association for Palliative Care (EAPC). Use of opioid analgesics in the

treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol

2012; 13:e58-68

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METHADONE

Introduction

Pharmacology of methadone

Chemical characteristics

Methadone is a synthetic opioid agonist with a chemical structure totally different from that of the

classical opium alkaloids such as morphine and codeine.

Methadone is used as a racemic mixture of levorotatory (L-methadone) and dextrorotatory (D-

methadone) isomers. For many years, the analgesic efficacy of methadone has been attributed

almost entirely to the action of L-methadone, whereas D-methadone was considered to be an

excipient. Recent findings indicate that D-methadone also contributes to the analgesic action of the

racemic mixture by blocking N-methyl-D-aspartate (NMDA) receptors [1-3].

Methadone is a basic drug, available as a hydrochloride salt in an aqueous solution that can be

administered by oral, parenteral, or rectal routes.

Pharmacodynamics

Several studies have demonstrated that the affinity of methadone to mu receptors is similar to that

of morphine [4]. Delta and k opioid receptor activation also produces analgesia. The affinity of

methadone for k receptors does not seem significantly different from that of morphine, but

methadone has a greater affinity for ∂ receptors than morphine does [5].

Moreover, unlike morphine, both isomers of methadone are able to block NMDA receptors. Finally,

the L-isomer of methadone inhibits the serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine

(NE) neuronal re-uptake [6]. Because both the blockage of NMDA receptors and the activation of

serotoninergic and noradrenergic pathways descending from the brainstem inhibit nociceptive

transmission [7,8], the analgesic action of methadone is probably mediated by synergistic

mechanisms different from those of morphine.

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Pharmacokinetics

Methadone is a lipophilic drug easily and rapidly absorbed by the gastrointestinal tract. Indeed, its

oral bioavailability is 80% (range, 41–99%). The peak plasma level occurs 4 hours after oral

administration [9,10]. Methadone has a large distribution volume with tissue binding higher than

protein binding, and accumulation occurs with repeated dosing; consequently adverse effects

related to methadone are delayed over the time because linked to methadone reabsorption from the

tissue. The protein binding of methadone has been shown to range from 60% to 90%. Methadone is

mainly bound to a1-acid glycoprotein (AAG). Because cancer is frequently associated with elevated

levels of AAG, the free fraction of methadone may vary significantly among cancer patients

[11,12]. Lower concentrations of AAG increase free plasma concentrations and the activity of

methadone. The greater lipid solubility of methadone explains its enhanced protein binding and its

considerable distribution and accumulation in tissues. The increased protein binding and tissue

accumulation in turn contribute to the prolonged retention of methadone in plasma, as is particularly

evident during repeated treatment. Methadone has been described as a drug with a rapid and

extensive distribution phase followed by a slow elimination phase. The terminal elimination half-

life varies from 13 to 58 hours (120 hours in some patients) [13]. In the liver, methadone undergoes

an extensive oxidative biotransformation through N-demethylation. In humans, the hepatic

extraction ratio indicates that less than 10% of methadone reaching the liver is extracted from the

blood [14].This value is similar to the value of free fraction of methadone in blood. Therefore, a

considerable change in the binding of methadone could alter the hepatic clearance of methadone.

The two major metabolites that result from hepatic biotransformation do not exert any

pharmacological activity [9]. In addition to the hepatic extraction, methadone is partially

metabolized in the intestinal wall by CYP3A4 enzyme [15]. The liver metabolism and fecal

excretion is the primary route of methadone elimination in most persons. Indeed, a significant

portion of the methadone that is filtered through the glomerulus is reabsorbed by the kidney, and

approximately 60% of methadone is eliminated by non-renal routes. Although a decreased urinary

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pH can significantly increase the renal clearance of methadone, the renal route is not a major route

of elimination if urine pH is above 6 [16].

Several studies have shown large variations among individuals in methadone pharmacokinetics. As

with the other opioids, no clear relationship between plasma concentrations and analgesic effects of

methadone has been established [17]. The main pharmacokinetic differences between morphine and

methadone are shown in Table 1. Of course, the dose adjustment is more difficult with methadone

than with a drug with a shorter half-life, such as morphine. For this reason, a good knowledge of

recently refined equianalgesic dose tables is important to achieve good pain management while

establishing the optimum methadone dose, especially in patients previously treated with morphine.

Drug interactions

In general, a drug interaction can be defined as one substance’s altering the effects of another drug

being administered at the same time [18]. Drug interactions can involve drugs and chemicals, drugs

and nutrients, or drug–drug interactions. Drug–drug interactions are the most significant and can be

broadly categorized as pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions may

produce changes in absorption, protein binding, distribution, biotransformation, and excretion.

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Pharmacodynamic interactions involve the drug mechanisms of action and usually can be predicted

and recognized more easily than pharmacokinetic interactions. As an example, the concomitant

administration of two drugs with depressant effects on the central nervous system (e.g., methadone

and a benzodiazepine) will increase the likelihood of negative effects caused by the inhibition of

brain functions (e.g., respiratory depression and sedation).

There are several interactions of methadone with the drugs most commonly used to treat cancer

patients, with particular reference to the interactions involving the cytochrome P-450 system in the

liver. A characteristic of low-extraction drugs such as methadone is that changes in hepatic

metabolism by induction or inhibition may significantly affect their clearance and elimination half-

life. Therefore, the probability of drug interaction is higher with methadone administration than

with morphine or other opioids. Unlike morphine, which is glucuronated, methadone is metabolized

by the cytochrome P-450 group of enzymes and does not produce active metabolites. The main

enzyme mediating N-demethylation of methadone in the liver is CYP3A4, with lesser involvement

of CYP1A2 and CYP2D6 [4,19]. Therefore, the most important interactions between methadone

and other drugs involve drugs that induce or inhibit CYP3A4 (Table 2). These drugs can reduce or

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increase methadone plasma concentrations. Because methadone strongly inhibits CYP2D6 [20], it

can reduce the hepatic biotransformation of drugs metabolized by this enzyme, such as the

neuroleptics haloperidol, domperidone, and risperidone and the tricyclic antidepressants. Table 3

shows the most important methadone drug interactions in clinical conditions. Although a drug–drug

interaction is more often produced by a drug capable of inhibiting or increasing hepatic metabolism,

an interaction can also be related to the concomitant administration of drugs that are metabolized by

the same CYP450 enzyme (eg, methadone and risperidone).

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References

1. Egbert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are

noncompetitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord.

Neurosci Lett 1995;187:165– 8.

2. Gorman AL, Elliot KJ, Taturisi CE, et al. The D- and L-isomers of methadone bind to the

noncompetitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and

spinal cord. Neurosci Lett 1997;223:5– 8.

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5. Jg L, Liao XP, Gong ZH, et al: The difference between methadone and morphine in

regulation of delta-opioid receptors underlies the antagonistic effect of methadone on

morphine-mediated cellular actions. Eur J Pharmacol 1999;373:233– 9.

6. Codd EE, Shank RP, Schupsky JJ, et al. Serotonin and norepinephrine uptake inhibiting

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Scand 1997;41:123– 32.

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Ther 1972;13:923–30.

23

10. Nilsson MI, Meresaar U, Anggard E. Clinical pharmacokinetics of methadone. Acta

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from alpha-1-acid glycoprotein. Clin Pharmacol Ther 1982;32:652–8.

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methadone to proteins in plasma of healthy volunteers: role of the variants of a1-acid

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by methadone. Br J Clin Pharmacol 1993;35:30 – 4.

24

Efficacy of Methadone in Clinical Studies

25

Figure 1. Consort – like report of Eligible Papers.

26

Summary of data for Efficacy (Table 1, Appendix 1).

Search Method

A literature review based on the guidance of the Centre for Reviews and Dissemination was

conducted.

An iterative approach was used starting with an electronic search of the MEDLINE database (via

PubMed – customized range date until November 8th, 2016. We considered all the eligible paper

published in the last five years (Figure 1). The generic search terms “methadone” AND “cancer

pain” were used. Citation tracking and search for all related eligible articles in PubMed were

performed. We identified 36 eligible paper for efficacy analysis with N=3 Randomized Controlled

Trials, N=8 Systematic Reviews, N=2 prospective open label studies, N=1 Observational Studies,

N=6 retrospective Studies, N=9 Case report /Case series and N=7 letter to the editor. Major

percentage of evidence came from systematic reviews, with about 22% of eligible papers.

Our report did not consider letters to the editor.

Levels of evidence analyzed may be graded down on the basis of study quality, imprecision,

indirectness (study PICO does not match questions PICO), because of inconsistency between

studies, or because the absolute effect size is very small; Level may be graded up if there is a large

or very large effect size. For more details please refer to the Oxford Centre for Evidence-Based

Medicine (http://www.cebm.net/index.aspx?o=5653).

Randomized Controlled Trials (Table 2, Appendix 1).

We identified N= 3 randomized controlled trials published between 2013 [1] and 2016 [2].

The first trial published by Poulain P et al. in 2016 (1) was a national, randomized, multicenter trial

aimed to compare two methadone titration methods (stop-and-go vs. progressive) in patients with

cancer-related pain who were inadequately relieved by or intolerant to Level 3 opioids where the

primary end point was the rate of success or failure at Day 4, defined as pain relief (reduction of at

27

least two points on the visual scale and a pain score <5 for two consecutive days) and no overdose

(Rudkin scale ≥3 and respiratory rate <8/minute). Pain relief was obtained in 80% and the rate of

success/failure was approximately 40% at Day 4 in both groups, with overdoses in 13% of the

patients throughout the study.

The second study published by Humann J et al. (2) was a randomised controlled trial versus

fentanyl performed with 52 strong opioids naive patients with head-and-neck cancer with pain

Numerical Rating Scale > 4 and a neuropathic pain component. The primary outcomes were

reduction in average pain, clinical success (defined as 50% average pain decrease) and reduction in

pain interference. Reduction in NRS was higher with the use of Methadone at 1, 3 and 5 weeks

(pain change 2.9, 3.1 and 3.1) compared to Fentanyl (1.4, 1.7 and 2.0). This difference was

significant at 1 (p = 0.011) and at 3 weeks (p = 0.03) and represented the first evidence of efficacy

of Methadone versus Fentanyl in cancer patients with a neuropathic pain component. The last study

was a RCT published by Lauretti GR et al. in 2013 in 722 cancer patients randomized to six groups

and prospectively studied to examine analgesia and adverse effects for 3 weeks (3) (please see

Table 2 for details). Epidural methadone plus lidocaine resulted in dose-dependent analgesia,

further improved by epidural dexamethasone, which also improved fatigue.

28

Systematic Review (Table 3, Appendix 1).

We identified N= 8 Systematic Reviews published between 2012 [3], 2014 [2], 2015 [2] and 2016

[1].

The first paper published by Taveros et al. in 2016 (4) regards a specific setting of pain

management i.e. the use of methadone for cancer pain in patients on treatment with methadone for

chronic substance abuse. The authors searched PubMed, PsychINFO, EMBASE, Clinical Key, the

Cochrane Library and CINAHL resulting in 680 hits with only 7 met inclusion criteria for the

study. Most of the studies favored the use of methadone either in scheduled divided doses every 4-8

hours or by continuous intravenous infusion. The conclusions were that treating MMT-maintained

patients with methadone for analgesia may be preferable to using other opioid analgesics, but he

overall strength of the evidence was poor, consisting mainly of case series. The second paper

published in 2015 by MC Lean S et al. (5) was a systematic review on the methods of rotation to

methadone from other opioids. Authors selected 25 of a total of 3214 identified potentially relevant

studies. As already observed, the evidence identified was mainly from uncontrolled observational

studies and studies were heterogeneous in methodology and outcome measures. One trial compared

three-day switch (3DS) and rapid conversion (RC) methods; two, 3DS; 10, RC; nine, ad libitum

(AL). Success rates were as follows: 3DS-93%, RC-71.7%, and AL-92.8%. The single clinical trial

and retrospective studies demonstrated poorer analgesia and an excess of adverse events in the RC

group (five dropouts because of AEs) compared with the 3DS group with no severe AEs). The three

days switch probably represent the best and safety rotation method.

Good P et al (6) conducted an important systematic review published in 2014 where the authors

analyzed the evidence for the use of methadone in cancer pain management. The authors conducted

a systematic literature search for randomized controlled trials (RCTs) published post the 2007

Cochrane review of methadone in cancer pain.

29

The studies used different routes of administration, dosing, initiation, and titration of methadone

and distinct pain scoring tools and did not address the issues raised by the Cochrane review.

Methadone has an important role in the management of cancer pain, with many advantages

including low cost, high oral bioavailability, rapid onset of action, once-daily dosing, and

postulated benefits in difficult pain control scenarios. However, due to limited research in this area,

methadone dosing remains a challenge, with vigilant dose initiation, adjustment, and monitoring

required.

Taberna M et al. carried out another systematic review in 2014 (7) focusing on the role of

methadone in pain management in elderly population. This was the first important review on this

setting. Only seven articles were obtained none of them specific to methadone use in elderly

patients with cancer. For these aspects, we can say that there are insufficient data on the use of

methadone as an analgesic in the elderly with cancer.

On this way, especially for opioids switching to methadone, we report the systematic review from

Mercadante S et al (8) were author conclusions were that existing data were not conclusive because

this aspect did not receive particular attention in most studies and age has not been found to be

independently associated with the dose ratio.

No more relevant adjunctive data about methadone were find by Koyyalagunta D et al (9) in their

systematic review. Authors reported that the evidence for methadone was poor based on low quality

studies with inconsistent results.

Due to the particular focus of the review and the poor level of evidence, we did not consider the

paper of Afsharimani et al and Ripamonti CI (Table 3) for our report.

30

Retrospective Studies (Table 4, Appendix 1).

We identified N= 6 Retrospective Studies published between 2012 [1], 2013 [1], 2015 [1] and 2016

[3].

Primary endpoints for these analyses were safety and efficacy/effectiveness (for one paper only).

All identified papers were uncontrolled retrospective analyses with heterogeneous methodology and

outcome measures.

The first study published in 2016 by Sugiyama Y et al. (10) regards the effectiveness on

management of neuropathic pain in 22 non-opioid naïve cancer patients with the mean FPS (FACE

Pain Scale) score reduction from 4.43 to 1.86, and methadone switching either reduced the number

of prescriptions or stopped them entirely in 12 out of 17 (70.5%) patients who had used adjuvant

analgesics before switching to methadone.

This was another evidence on neuropathic pain relief with methadone in cancer patients, as just

reported by Haumann J et al. (2) (Table 1).

Courtemanche F et al. reported the efficacy and safety on the use of Methadone as co-analgesic in

the management of cancer pain (11). A cohort of 146 patients was followed retrospectively for up to

60 days with 49% of them qualified as significant responders (≥30% reduction in pain intensity).

No clear data was available about cumulative dosing of methadone and, as reported by author, there

was a substantial amount of missing data.

Similar data on the use of methadone as co-analgesic drug in the management of cancer pain came

from the analysis of Salpeter et al. (12,13).

Author reports the use of low dose of methadone (median daily dose, 5 mg) in association with

haloperidol for pain control patients underwent conversion from another opiate without dose

escalation or opioid-induced hyperalgesia.

Finally, another important analysis came from the retrospective study of Peirano GP et al. (14) on

the safety and efficacy of methadone in a developing country palliative care unit as first line

31

treatment as an helpful palliative strategy in low-resources countries given its long-acting effect at

low cost.

Prospective Open Label studies; Observational studies (Table 5, Appendix 1).

We identified N= 2 Prospective Open-label Studies and N=1 Observational Study.

All identified papers were very heterogeneous for outcome measures evaluation tools.

Primary end-point for all these studies was the efficacy and safety of Opioid rotation to methadone

for refractory cancer pain.

The most important study was published by Porta Sales J et al. in 2016 (15). This was a Prospective

Open-label Studies of 145 patients whose treatment was rotated from other opioids to methadone.

Main outcome measure was change in the variable "worst pain" at day 28 with Brief Pain

Inventory.

Rotation to methadone was performed for the following reasons: poor pain control (77.9%), opioid

side effects (2.1%), or both (20%). The mean daily oral morphine equivalent dose before rotation

was 193.7 mg. The median worst and average pain scores decreased significantly (p < .0001) from

baseline to day 28: The median worst pain score decreased from 9 (interquartile range [IQR]: 8-10)

to 6 (IQR: 3-8), and the median average pain score decreased from 6 (IQR: 5-7) to 4 (IQR: 2-5).

The proportions of patients with moderate to severe worst and average pain decreased by 30.3%

and 47.5%, respectively, by day 28. No increase in opioid toxicity was observed during the study.

The results of this study, conducted prospectively under real clinical conditions, support the

efficacy and safety of oral methadone as a second-line opioid in ambulatory patients with cancer.

Data from the other reported trials (Table 5) are similar to the Porta Sales’ ones.

32

Case Report; Case Series (Table 6, Appendix 1).

We identified N= 10 Case Reports/Case Series published from 2012 [3], 2013 [5], 2014 [1] to 2015

[1].

Three of them regarded the safety and efficacy of the intra-venous administration of Methadone.

One of them (Rasmussen VF et al – 16) reported two case report of high dose of IV methadone in

pediatric cancer patients.

Similar to the analyzed data in our report, two studies reported the efficacy of Methadone as co-

analgesic drug in the management of refractory cancer pain (17,18) and two other studies (19,20)

analyzed the switching to methadone from other opioids.

Globally, presented data are in line with other reported results with high level of evidence.

33

References

1. Poulain P, Berleur MP, Lefki S et al. Efficacy and Safety of Two Methadone Titration Methods

for the Treatment of Cancer-Related Pain: The EQUIMETH2 Trial (Methadone for Cancer-

Related Pain). J Pain Symptom Manage. 2016 Nov;52(5):626-636.e1. doi:

10.1016/j.jpainsymman.2016.05.022. Epub 2016 Sep 30.

2. Haumann J, Geurts JW, van Kuijk SM, Kremer B, Joosten EA, van den Beuken-van Everdingen

MH.Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-

neck cancer.Eur J Cancer. 2016 Sep;65:121-9. doi: 10.1016/j.ejca.2016.06.025.

3. Lauretti GR, Rizzo CC, Mattos AL, Rodrigues SW.Epidural methadone results in dose-

dependent analgesia in cancer pain, further enhanced by epidural dexamethasone. Br J Cancer.

2013 Feb 5;108(2):259-64. doi: 10.1038/bjc.2012.593.

4. Taveros MC, Chuang EJ. Pain management strategies for patients on methadone maintenance

therapy: a systematic review of the literature. BMJ Support Palliat Care. 2016 Aug 26. pii:

bmjspcare-2016-001126. doi: 10.1136/bmjspcare-2016-001126. [Epub ahead of print] Review.

5. McLean S, Twomey F.Methods of Rotation From Another Strong Opioid to Methadone for the

Management of Cancer Pain: A Systematic Review of the Available Evidence. J Pain Symptom

Manage. 2015 Aug;50(2):248-59.e1. doi: 10.1016/j.jpainsymman.2015.02.029. Review.

6. Good P, Afsharimani B, Movva R, Haywood A, Khan S, Hardy J.Therapeutic challenges in

cancer pain management: a systematic review of methadone. J Pain Palliat Care Pharmacother.

2014 Sep;28(3):197-205. doi: 10.3109/15360288.2014.938883. Review.

34

7. Taberna M, Villavicencio-Chávez C, González-Barboteo J.[Use of methadone in the elderly

with cancer pain: a systematic review]. Rev Esp Geriatr Gerontol. 2014 May-Jun;49(3):129-36.

doi: 10.1016/j.regg.2013.08.002. Review. Spanish.

8. Mercadante S, Bruera E.The effect of age on opioid switching to methadone: a systematic

review. J Palliat Med. 2012 Mar;15(3):347-51. doi: 10.1089/jpm.2011.0198. Review.

9. Koyyalagunta D, Bruera E, Solanki DR, Nouri KH, Burton AW, Toro MP, Bruel BM,

Manchikanti L. A systematic review of randomized trials on the effectiveness of opioids for

cancer pain. Pain Physician. 2012 Jul;15(3 Suppl):ES39-58. Review.

10. Sugiyama Y, Sakamoto N, Ohsawa M, Onizuka M, Ishida K, Murata Y, Iio A, Sugano K,

Maeno K, Takeyama H, Akechi T, Kimura K.A Retrospective Study on the Effectiveness of

Switching to Oral Methadone for Relieving Severe Cancer-Related Neuropathic Pain and

Limiting Adjuvant Analgesic Use in Japan. J Palliat Med. 2016 Oct;19(10):1051-1059.

11. Courtemanche F, Dao D, Gagné F, Tremblay L, Néron A.Methadone as a Coanalgesic for

Palliative Care Cancer Patients. J Palliat Med. 2016 Sep;19(9):972-8. doi:

10.1089/jpm.2015.0525.

12. Salpeter SR, Buckley JS, Buckley NS, Bruera E.The use of very-low-dose methadone and

haloperidol for pain control in the hospital setting: a preliminary report. J Palliat Med. 2015

Feb;18(2):114-9. doi: 10.1089/jpm.2014.0266.

35

13. Salpeter SR, Buckley JS, Bruera E.The use of very-low-dose methadone for palliative pain

control and the prevention of opioid hyperalgesia.J Palliat Med. 2013 Jun;16(6):616-22. doi:

10.1089/jpm.2012.0612.

14. Peirano GP, Mammana GP, Bertolino MS, Pastrana T, Vega GF, Russo J, Varela G, Vignaroli

E, Ruggiero R, Armesto A, Camerano G, Dran G. Methadone as first-line opioid treatment for

cancer pain in a developing country palliative care unit. Support Care Cancer. 2016

Aug;24(8):3551-6. doi: 10.1007/s00520-016-3191-5. Epub 2016 Mar 29.

15. Porta-Sales J, Garzón-Rodríguez C, Villavicencio-Chávez C, Llorens-Torromé S, González-

Barboteo J.Efficacy and Safety of Methadone as a Second-Line Opioid for Cancer Pain in an

Outpatient Clinic: A Prospective Open-Label Study. Oncologist. 2016 Aug;21(8):981-7. doi:

10.1634/theoncologist.2015-0503.

16. Rasmussen VF, Lundberg V, Jespersen TW, Hasle H.Extreme doses of intravenous methadone

for severe pain in two children with cancer.Pediatr Blood Cancer. 2015 Jun;62(6):1087-90. doi:

10.1002/pbc.25392. Epub 2015 Jan 13.

17. Wallace E, Ridley J, Bryson J, Mak E, Zimmermann C.Addition of methadone to another

opioid in the management of moderate to severe cancer pain: a case series. J Palliat Med. 2013

Mar;16(3):305-9. doi: 10.1089/jpm.2012.0335.

18. Leppert W, Kowalski G.Methadone as an additional opioid for a cancer patient with severe

neuropathic and bone pain not responsive to other opioids and adjuvant analgesics. J Palliat

Care. 2013 Summer;29(2):119-21.

36

19. Kilonzo I, Twomey F.Rotating to oral methadone in advanced cancer patients: a case series. J

Palliat Med. 2013 Sep;16(9):1154-7. doi: 10.1089/jpm.2012.0594.

20. Mercadante S, Ferrera P, Arcuri E, Casuccio A.Opioid-induced hyperalgesia after rapid titration

with intravenous morphine: Switching and re-titration to intravenous methadone. Ann Palliat

Med. 2012 Apr;1(1):10-3. doi: 10.3978/j.issn.2224-5820.2012.01.02.

37

Toxicities of Methadone in Clinical Studies

Figure 1. Search for Toxicity.

38

Summary of data for Toxicity (Table 1, Appendix 2).

Search Method


conducted.



published in the last five years (Figure 1). The generic search terms “methadone” AND “cancer

pain” were used. Citation tracking and search for all related eligible articles in PubMed were

performed. We identified 36 eligible paper for toxicity analysis with N=2 Reviews, N=1

Observational Studies, N=2 retrospective Studies, N=3 Case report /Case series Major percentage

of evidence came from case reports.






39

Review (Table 2, Appendix 2).

We identified N= 2 reviews published between 2013 [1] and 2016 [1].

The first paper published in 2014 by Dowson c et al. (1) focus on the development of developed

bilateral peripheral edema from methadone in the in patient with ependymoma with low back and

scrotal pain. In the associated review, authors explored the possible underlying mechanisms.

There have been cases published reporting the development of edema with methadone maintenance

therapy but no cases on the association with methadone and peripheral edema in the palliative care

setting.

Following cessation of methadone peripheral edema was resolved.

The second paper published by Dahan A et al. (2) analyzed the opioid-induced respiratory

depression associated with the use of methadone.

This is a review from thirty-four reports describing 42 chronic pain patients experiencing opioid-

induced respiratory depression. Cases published before the year 2000 (pre-2000) predominantly

involved morphine in cancer patients, whereas cases since 2000 (post-2000) predominantly

involved methadone or transdermal fentanyl in non-cancer pain patients. Specific factors that

contributed to OIRD were elevated opioid plasma levels due to renal impairment and sensory

deafferentiation in pre-2000 cases, and elevated plasma levels due to drug interactions on the

cytochrome P450 in post-2000 cases. Due to the setting (chronic non cancer pain), we reported the

data only for pharmacovigilance info on the use of methadone, but there are not reviews or

systematic reviews particularly focused on cancer patients.

40


We identified N= 2 retrospective studies published between 2013 [1] and 2016 [1].

Cardiac toxicities from methadone are one of the most reported toxicities from this drug.

Methadone prolongs cardiac conduction, from mild corrected QT (QTc) prolongation to torsades de

pointes and ventricular fibrillation, in adults. However, methadone use for pain and its effects on

cardiac conduction have not been investigated in pediatric populations.

Anghelescu DL et al. (3) published in 2016 a retrospective review of QTc intervals in patients

receiving methadone in a 4-years observation period.

Of the 61 patients who received methadone, 37 met our inclusion criteria and underwent 137

electrocardiograms (ECGs). During methadone treatment, the mean QTc was longer than that at

baseline (446.5 vs. 437.55 ms). The mean methadone dose was 27.0±24.3 mg/d (range, 5-125 mg/d;

median, 20 mg/d) or 0.47±0.45 mg/kg per day (range, 0.05-2.25 mg/kg per day; median, 0.37

mg/kg per day), and the mean duration of therapy was 49 days. The authors identified a correlation

between automated and manual ECG readings by two cardiologists (Pearson r=0.649; p<0.0001),

but the authors found no correlations between methadone dose or duration and concurrent QTc-

prolonging medications, sex, age, electrolyte abnormalities, or renal or hepatic dysfunction. Authors

concluded that at a clinically effective analgesic dose, methadone dosage and duration were not

correlated with QTc prolongation, even in the presence of other risk factors, suggesting that

methadone use may be safe in pediatric populations.

Second study published by Moryl N et al. in 2013 (4) focused on metabolic toxicities from

methadone, analyzing whether or not rapid methadone dose increase can be associated with onset of

hypoglycemia by a retrospective chart review of 59 consecutive opioid-tolerant patients with cancer

who received methadone for pain while inpatients in a tertiary cancer center. Eleven patients had

hypoglycemia while receiving methadone, of them two patients had at least two episodes of

hypoglycemia. In the 11 cases of documented hypoglycemia, mean methadone dose was nearly

41

doubled (92 percent increase) within 2 days before the onset of hypoglycemia. None of the other

recorded factors correlated with glucose level in this group of patients. Authors concluded that a

patient who develops unexplained sweating, palpitations, or lethargy during methadone titration

may benefit from blood glucose monitoring.

Observational Studies (Table 4, Appendix 2).

We identified N= 2 observational studies published between 2013

As previously reported in our analysis, cardiac toxicities from methadone are one of the most

reported toxicities.

All the identified observational studies analyzed focused on cardiac toxicity, particularly on

prolonged QTc interval.

Most recent retrospective study (3) demonstrated that at a clinically effective analgesic dose,

methadone dosage and duration were not correlated with QTc prolongation, even in the presence of

other risk factors.

In their prospective study, van den Beuken-van Everdingen MH et al. (5) in a period of 3 years,

while 130 patients used methadone as pain treatment at a stable dose for at least 1 week, 12-lead

electrocardiograms (ECGs) were performed. Corrected QT times, demographic features, methadone

dose, duration of therapy, and relevant co medication were documented. The study found that in our

patients with pain, with relatively low doses of methadone, 5 percent had QTc times ≥500 ms and

were thus at serious at risk for TdP. ECGs have to be made in all patients with methadone therapy 1

week after introducing methadone.

No additional data were found in the study of Mercadante et al. (6).

We can conclude that, about cardiac safety, evidences are poor and not clear and we think that more

studies are required.

42

Case Reports/Case Series (Table 5, Appendix 2).

We identified N= 3 observational studies published between 2012 [2] and 2013 [1].

After full text paper analysis, we excluded 2/3 studies from our report because the setting was the

chronic non-cancer pain management.

We considered only the case reported by Amos LB et al. (7) about severe central sleep apnea in a

child with leukemia as serious adverse effect from chronic methadone therapy. Due to the general

conditions of the patient with chemotherapy-related cerebral atrophy and renal insufficiency, we

think that impaired methadone clearance may have also contributed to the severity of his sleep-

disordered breathing. Maintenance methadone treatment is not a common pediatric practice;

therefore, the adverse effects of methadone therapy, are rarely reported in children and the use of

this drug in the pediatric population need trained expertise on pain management.

43

References

1. Dawson C, Paterson F, McFatter F, Buchanan D.Methadone and oedema in the palliative

care setting: a case report and review of the literature. Scott Med J. 2014 May;59(2):e11-3.

doi: 10.1177/0036933014530057. Review.

2. Dahan A, Overdyk F, Smith T, Aarts L, Niesters M.Pharmacovigilance: a review of opioid-

induced respiratory depression in chronic pain patients. Pain Physician. 2013 Mar-

Apr;16(2):E85-94. Review.

3. Anghelescu DL, Patel RM, Mahoney DP, Trujillo L, Faughnan LG, Steen BD, Baker JN,

Pei D.Methadone prolongs cardiac conduction in young patients with cancer-related pain. J

Opioid Manag. 2016 May-Jun;12(2):131-8. doi: 10.5055/jom.2016.0325.

4. Moryl N, Pope J, Obbens E. Hypoglycemia during rapid methadone dose escalation. J

Opioid Manag. 2013 Jan-Feb;9(1):29-34. doi: 10.5055/jom.2013.0144.

5. van den Beuken-van Everdingen MH, Geurts JW, Patijn J.Prolonged QT interval by

methadone: relevance for daily practice? A prospective study in patients with cancer and

noncancer pain. J Opioid Manag. 2013 Jul-Aug;9(4):263-7. doi: 10.5055/jom.2013.0167.

6. Mercadante S, Prestia G, Adile C, Casuccio A.Changes of QTc interval after opioid

switching to oral methadone. Support Care Cancer. 2013 Dec;21(12):3421-4. doi:

10.1007/s00520-013-1928-y.

7. Amos LB, D'Andrea LA.Severe central sleep apnea in a child with leukemia on chronic

methadone therapy. Pediatr Pulmonol. 2013 Jan;48(1):85-7. doi: 10.1002/ppul.22539.

44

Clinical considerations on Methadone

Methadone is an old drug (1) considered to be a useful alternative to oral morphine, hydromorphone

and transdermal fentanyl in treating moderate to severe cancer –related pain and extensive reviews

on the subject have been published in recent years (2-4).

Oral methadone provides the potential to control pain that does not respond to morphine or other

opioids because methadone shows incomplete cross-tolerance with other µ-opioid receptor agonist

analgesics (5-11). Moreover, there is the possibility of using it instead of other opioids when

accumulation of active metabolite is the cause of side effects such as myoclonus, sedation,

confusion, nausea and vomiting (5-11). Although morphine and methadone demonstrate

approximately the same analgesic potency after single dose administration, in switching from one

opioid to methadone a reduction of the equianalgesic dose by one-fourth to one-twelfth is

recommended (12,13). Methadone represents an effective alternative to oral morphine, but more

caution is needed in its administration, compared with other opioids, because of marked inter-

individual differences in its half-life in plasma. This is the main reason why attention is required

when using this drug in treating chronic cancer pain.

The low cost of methadone paradoxically may contribute to the limited knowledge of its

characteristics and to the restricted therapeutic use of this drug because of the little financial

incentive for pharmaceutical companies to invest in research or to disseminate scientific

information. The low cost of methadone, is of great importance for its ability in developing

countries (14).

For the strength of evidences reported, we can conclude that in the last five years there was a lot of

published paper on this setting. However, quality of these study remains poor, today methadone still

represent a good and efficacious treatment on the management of cancer pain in specific conditions.

45

References

1. Ripamonti C, Bianchi M. The use of methadone for cancer pain. Hematol Oncol Clin North Am

2002;16:543-555.

2. Good P, Afsharimani B, Movva R, Haywood A, Khan S, Hardy J. Therapeutic changes in

cancer pain management: a sistematic review of methadone. J Pain Palliat Care Pharmacother

2014;28:197-205

3. Mercadante S, Bruera E. Opioid switching in cancer pain: From the beginning to nowadays.

Crit Rev Oncol Hematol. 2016;99:241-8

4. Taberna M, Villavicencio-Chávez C, González-Barboteo J.[Use of methadone in the elderly

with cancer pain: a systematic review]. Rev Esp Geriatr Gerontol. 2014 May-Jun;49(3):129-36.

doi: 10.1016/j.regg.2013.08.002. Review. Spanish.

5. Haumann J, Geurts JW, van Kuijk SM et al. Methadone is superior to fentanyl in treating

neuropathic pain in patients with head & neck cancer. Eur J Cancer 2016;65:121-9.

6. Fitzgibbon DR, Ready LB. Intravenous high-dose methadone administered by patient controlled

analgesia and continuous infusion for the treatment of cancer pain refractory to high-dose

morphine. Pain 1997;73:259-261.

7. Mercadante S, Casuccio A, Fulfaro F, et al. Switching from morphine to methadone to improve

analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol 2001;19:2898-

2904.

8. de Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal

cancer patients. J Pain Symptom Manage 1995;10:378-384.

9. Ventafridda V, Ripamonti C, Bianchi M, Sbanotto A, De CF. A randomized study on oral

administration of morphine and methadone in the treatment of cancer pain. J Pain Symptom

Manage 1986;1:203-207.

10. Mercadante S, Casuccio A, Agnello A, et al. Morphine versus methadone in the pain treatment

of advanced-cancer patients followed up at home. J Clin Oncol 1998;16:3656-3661.

https://www.ncbi.nlm.nih.gov/pubmed/26806145

46

11. Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid

for cancer pain: a randomized, double-blind study. J Clin Oncol 2004;22:185-192.

12. Ripamonti C, Groff L, Brunelli C, et al. Switching from morphine to oral methadone in treating

cancer pain: what is the equianalgesic dose ratio? J Clin Oncol 1998;16:3216-3221.

13. Mercadante S, Casuccio A, Calderone L. Rapid switching from morphine to methadone in

cancer patients with poor response to morphine. J Clin Oncol 1999;17:3307-3312.

14. Peirano GP, Mammana GP, Bertolino MS, Pastrana T, Vega GF, Russo J, Varela G, Vignaroli

E, Ruggiero R, Armesto A, Camerano G, Dran G. Methadone as first-line opioid treatment for

cancer pain in a developing country palliative care unit. Support Care Cancer. 2016

Aug;24(8):3551-6. doi: 10.1007/s00520-016-3191-5. Epub 2016 Mar 29.

47

TRANSDERMAL FENTANYL SYSTEM (TTS)

Introduction

Pharmacokinetics and Pharmacodynamics

Substances with high lipid solubility and molecular weight below 800-1000 daltons (kDa) can pass

through the skin. The absorption rate varies according to different factors such as the type of the

vehicle, the skin characteristics (the thickness of stratum corneum), conditions, presence of

cachexia, body surface (1).

In general drugs that are successfully administered transdermally are those in which the daily dose

is very low (no more than a few milligrams). Patient compliance with this route of administration is

excellent, and skin reactions are rarely observed. Among opioids, the potent synthetic drug fentanyl

citrate is particularly suitable for transdermal administration, and its utility in pain therapy has been

extensively evaluated. Pharmacokinetic studies demonstrated that the rate of absorption of fentanyl

from the transdermal delivery is constant beginning 4-8 h after placement of the patches. Steady

state is reached on the third day. However, a wide individual variability exists (2). There is a lag

period after patch application before plasma concentrations approach therapeutic levels. This lag

period is highly variable, with a mean value of about 13 h (3). Fentanyl is metabolized in the liver

primarily (> 75%) by CYP3A4 to inactive norfentanyl (4). Fentanyl renal clearance accounts for

less than 10% of the dose (5, 6). Fentanyl is ~ 80% bound in plasma to albumin and α1-acid

glycoprotein (7). Intravenous and Transdermal fentanyl clearance is reduced by impaired liver

function and co administration of CYP3A4 inhibitors and increase with co administration of

CYP3A4 inducers (8,9). The transdermal fentanyl works till 72 hours. However, published data

show that application intervals have to be shortened in about 25% of patients (10) at 48-60 hours

because on the 3rd day of each patch period the need of rescue doses of short release oral morphine

was major of 1st and 2nd day (10,11). In 11 to 43% of patients during long-term treatment, the

patch had to be changed every 48 h (12).

48

The effectiveness of TTS fentanyl was first demonstrated in postoperative pain. Especially for the

high incidence of respiratory depression, this use is now contraindicated. Conversely, in stable,

chronic, cancer pain this formulation offers an interesting alternative to oral morphine. In

comparison with oral morphine TTS fentanyl seem to cause fewer gastrointestinal side effects, with

special reference to constipation (13,14). Of course, this formulation is contraindicated during the

titration phase, or to control breakthrough pain.

The permeability coefficient for fentanyl is affected by temperature. A rise in body temperature to

40 ºC may increase the absorption rate by about one-third (13). Acute toxicity related to increased

absorption secondary to high temperature has been reported (14). A recent study in volunteers

demonstrated that the application of local heat to the transdermal patch significantly increase

systemic delivery of fentanyl (15).

Four cases of death due to the intravenous injection of fentanyl extracted from transdermal patches

have been reported (125).

To minimize the problem of the “dose-dumping” due to membrane damage, and the risk of illegal

diversion, a transdermal matrix patch formulation of fentanyl has been developed (16).

49

References

1. Trobec K, Kerec Kos M, von Haehling S, Springer J, Anker SD, Lainscak M.

Pharmacokinetics of drugs in cachectic patients: a systematic Review. PLOS ONE 2013;

8/11: e79603. doi:10.1371/journal.pone.0079603

2. Grond S, Radbruch L, Lehmann KA. Clinical pharmacokinetics of transdermal opioids:

focus on transdermal fentanyl. Clin Pharmacokin 2000; 38: 59-89.

3. Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet Oncology 2001; 2:

165-72.

4. Labroo RB, Paine MF, Thummel KE, Kharash ED. Fentanyl metabolism by human hepatic

and intestinal cytochrome P450 3A4: implications for interindividual variability in

disposition, efficacy, and drug interactions. Drug Metab Dispos 1997; 25: 1072-1080

5. Mather LE. Clinical pharmacokinetics of fentanyl and its newer derivatives. Clin

Pharmacokinet 1983; 8:422-446

6. DePriest AZ, Puet BL, Holt AC, Roberts A, Cone EJ. Metabolism and dispositionof

prescription oppioids: a review. Forensic Sci. Rev. 2015; 27; 115-145

7. Bower S. Plasma protein binding of fentanyl. J Pharm Pharmacol 1981; 33:507-514

8. Bernard SA, Bruera E. Drug interactions in palliative care. J Clin Oncol 2014; 18:1780-

1799

9. Kokubun H, Ebinuma K, Matoba M, Takayanagi R, Yamada Y, Yago K. Population

pharmacokinetics of transdermal fentanyl in patients with cancer-related pain. J Pain Palliat

Care Pharmacother 2012; 26: 98-104

10. Portenoy RK, Southam MA, Gupta SK, Lapin J, Layman M, Inturrisi CE, Foley KM.

Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics. Anesthesiology

1993; 78/1: 36-43

50

11. Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet Oncology 2001; 2:

165-72

12. Grond S, Radbruch L, Lehmann KA. Clinical pharmacokinetics of transdermal opioids:

focus on transdermal fentanyl. Clin Pharmacokin 2000; 38: 59-89

13. Kornick CA, Santiago-Palma J, Moryl N, Payne R, Obbens EA. Benefit-risk assessment of

transdermal fentanyl for the treatment of chronic pain. Drug Saf 2003; 26: 951-73

14. Rose PG, Macfee MS, Boswell MV. Fentanyl transdermal system overdose secondary to

cutaneous hyperthermia. Anesth Analg 1993; 77: 390-1.

15. Ashburn MA, Ogden LL, Zhang J, Love G, Basta SV. The pharmacokinetics of transdermal

fentanyl delivered with and without controlled heat. J Pain 2003; 4: 291-7.

16. Saito T, Fujii M, Saito S, Shimada K, Fujiwara K, Koboyashi K. Pharmacokinetics of a new

fentanyl tape with a novel delivery system of Transdermal Matrix patches in patients with

cancer pain. Oncology 2014; 86:10-1.

51

Efficacy of Transdermal Fentanyl in clinical Studies.

Figure 1. Consort – like report of Eligible Papers for Efficacy.



conducted.



published in the last five years (Figure 1). The generic search terms (“fentanyl” AND “cancer

pain”) were used. Citation tracking and search for all related eligible articles in PubMed were

performed. We identified 19 eligible paper for efficacy analysis with N=1 Randomized Controlled

Trials, N=4 Reviews, N=7 prospective open label studies, N=7 Retrospective Studies. We did not

52

find case reports/case series. Major percentage of evidence came from prospective open-label

studies and retrospective studies reviews, with about 74% of eligible papers. Our report did not

consider letters to the editor.





Medicine (http://www.cebm.net/index.aspx?o=5653)

Randomized Trial (Table 2, Appendix 3).

In the last five years literature search, only one randomized controlled trial was identified.

The study was published by Raptis E et al. in 2014 (1) and was a randomized open – label trial on

the use of pregabalin versus opioids for the treatment of neuropathic cancer pain. Patients were

randomized into two groups and received increasing doses of either oral pregabalin or transdermal

fentanyl for 28 days. VAS score, patient satisfaction, need for opioid rescue, and adverse events

were recorded.

In the pregabalin group, a significantly higher proportion of patients achieved at least 30%

reduction in VAS compared with the fentanyl group (73.3%, 95% CI: 60.3%-83.93 vs. 36.7%, 95%

CI: 24.5%-50.1%, P < 0.0001, respectively), while the percentage mean change from baseline was

also significantly different [46% (95% CI: 39.5%-52.8%) for pregabalin and 22% (95% CI: 14.9%-

29.5%) for fentanyl (P < 0.0001)]. Patient-reported satisfaction was more frequent with pregabalin,

while adverse events and treatment discontinuations were more frequent in the fentanyl group. We

can say that a prompt use of a neuropathic pain-specific adjuvant, such as pregabalin may lead to

better control of the neuropathic component, with opioid-sparing effects. However, trans-dermal

fentanyl still remains the optimal choice for pain management.

53


We identified N= 7 Retrospective Studies published between 2011 [1], 2013 [1], 2015 [1] and 2016

[4].

Main intervention of these studies was the opioid switching to TDF in advanced cancer patients.

The objective of these analyses was the opioids conversion ratio (for four paper) and the safety and

efficacy of TDF formulations.

The most recent study published by Reddy A et al. in 2016 (2) reviewed 2471 consecutive patient

visits (938 patients) to determine the opioid rotation ratio of TDF to strong opioids, as measured by

morphine equivalent daily dose (MEDD).

The same authors published in 2016 another important retrospective analysis on 6790 consecutive

patients from 2010 to 2013 to identify those who underwent rotation from other opioids to TDF (3).

In total, 129 patients underwent opioid rotation from other opioids to TDF. The mean patient age

was 56 years, 59% were men, and 88% had advanced cancer. Uncontrolled pain (80%) was the

most frequent reason for opioid rotation. In 101 patients who underwent opioid rotation and had no

worsening of pain at follow-up, the median ORR from net MEDD to TDF (in mg per day) was 0.01

(range, -0.02 to 0.04), and the correlation coefficient of the TDF dose to the net MEDD was 0.77 (P

< .0001). The ORR was not significantly impacted by body mass index or serum albumin. The ORR

of 0.01 suggests that an MEDD of 100 mg is equivalent to 1 mg TDF daily or approximately 40

micrograms per hour of TDF (1000 micrograms/24 hours). On this way, another similar study was

published in the same year by Matsumura C. et al. (4) about conversion ratio and adequate fentanyl

dose in 122 patients with cancer pain in opioid switching from oral oxycodone.

We can say that we should carefully and rapidly control pain in opioid switching based on the

adequate dose indicated in these studies.

54

Two papers analyzed safety and efficacy of once-a-day TDF formulations (5,6). Data supports the

use of this formulation as a dominant strategy for patients receiving a 72-h transdermal fentanyl not

lasting 72 h.

The last study considered in Our report regards data published by Bilen A. et al in 2012 (7) about

the use of TDF among geriatric population in 181 patients. Demographic data, cancer type, duration

of pain, side effects, visual analog scale (VAS) score, treatment assessment scale (TAS) score, TDF

dosage, and the number of patients in whom therapy has been terminated were recorded. After the

usage of TDF, reduction in pain score was observed in both groups (p<0.001). The TAS score was

similar between the groups at the end of the first month, but it was lower in Group G in the

following months. Constipation, dry mouth, somnolence, and dyspnea were seen more frequently in

Group G. Because of these side effects, the number of patients in whom therapy was terminated

was higher in Group G. Authors concluded that the TDF patch is a good choice for cancer pain

treatment for both adult and geriatric patients. Since it was observed that the incidence of side

effects was higher in the geriatric patients, they should be treated more carefully.

55

Prospective Open-label Studies; Observational Studies (Table 4, Appendix 3).

We identified N= 4 Prospective open-label studies published between 2011 [1], 2014 [1], 2015 [1]

and 2016 [1] and N=3 Observational Studies published from 2012 [1], 2014 [1] and 2015 [1].

The first prospective open-label studies analyzed (8) the use of Transdermal Fentanyl for pain

management in Opioid-Naive Pediatric Cancer Patients where sixty-four male and female pediatric

patients with moderate to severe chronic cancer pain, ages ranging 2-14 years, were included.

Patients were observed for pain relief using the Visual Analog Scale and the Wong-Baker FACES

Pain Rating Scale, play performance score, and for side effects. There was significant improvement

of visual analog scale and FACES pain scores from the baseline to the second day of application

(P < 0.001). By the 15th day, scores reached 1.18 ± 0.393 and 1.13 ± 0.35, respectively (P < 0.001).

Play performance scale improved from the third day of application of the patch when compared

with the baseline (P < 0.001), reaching 55.02 ± 8.35 (P < 0.001) at the end of the study. The

sedation score increased on the second day to 2 in 10 patients and to 3 in 54 patients. By the

seventh day, 56 patients had a sedation score of 1. All patients returned to baseline by the 15th day.

Itching was reported in 16 cases, and erythema occurred in 10 cases. No significant side effects

were reported.

Kang JH described similar data in 2015 (9) on the efficacy of low-dose transdermal fentanyl in

opioid-naive cancer patients with moderate-to-severe pain. Low-dose TDF was an effective

treatment for patients with cancer pain of moderate-to-severe intensity.

Data reported from Zhu YL et al (10) on the use of new formulation of TDF among Chinese

population did not discord with all reported ones, but not all the patients were opioid naïve.

The other analyzed papers regarded the opioid switching to TDF. We reported two observational

studies and one prospective open-label study. The last one, published by Minami S in 2014 (11)

was an open-label two-centered prospective study in patients with thoracic malignancy suffering

persistent malignancy-related pain with numeric rating scale of pain intensity ≤ 3 which had been

56

controlled by oral oxycodone ≤ 20 mg/day. Eligible patients switched from oral oxycodone to

12.5 μg/h of transdermal fentanyl matrix patch. The dose was allowed to be titrated upwards every

3 day by 25-50%, except for the first increase from 12.5 μg/hr to 25 μg/hr, until achieving adequate

pain control. The data on patients' global assessment scores measured on a five-step scale, an 11-

point numeric rating scale of pain intensity, the severity of adverse effects using a four-point

categorical rating scale, and the Epworth sleepiness scale questionnaire were collected for 15 days.

Forty-nine eligible patients were analyzed. Overall patients' satisfaction score significantly

improved from day 1 (2.7 ± 0.9) to day 15 (2.3 ± 0.9) (p < 0.05), and 90% and 78% of patients

remained to receive the minimum dose of fentanyl patch on day 8 and 15 from the opioid switch.

There was a significant difference in sleepiness throughout the study period, though no difference

was detected in pain intensity and other adverse effects.

No significant data were reported from the other two observational studies (Table 4).

Systematic Reviews and Non-Systematic reviews (Table 5, Appendix 3).

We identified N= 2 Systematic Reviews and N=2 other non-systematic reviews published between

2012 [1], 2013 [1] and 2014 [2].

We did not find papers published in the last two years.

The most important evidence came from the Cochrane Systematic Review on the use of transdermal

fentanyl for cancer pain published in 2013 (12) to determine the analgesic efficacy of transdermal

fentanyl for relief of cancer pain and to assess the adverse events associated with the use of

transdermal fentanyl for relief of cancer pain. There were 1244 participants randomised in

classically designed RCTs, of whom 1197 had evaluable data, and 138 patients enrolled in an

enriched enrolment, randomised withdrawal (EERW) trial. Overall, 600 participants were treated

with transdermal fentanyl patches, 382 with various formulations of morphine, 36 with methadone,

and 221 with paracetamol plus codeine. There were major sources of potential bias, including lack

57

of blinding, small size, high levels of attrition, and inconsistent reporting. There were insufficient

comparable data for meta-analysis to be undertaken or to produce numbers needed to treat (NNT)

for the analgesic effect. In seven studies with 461 participants reporting pain intensity results after

about two weeks, the mean or median pain scores were on the borderline of mild and moderate

pain. Most participants would have had no worse than mild pain on treatment. Another reported that

77% of participants using transdermal fentanyl had an undefined successful outcome. Fewer

participants experienced constipation with transdermal fentanyl (28%) than with oral morphine

(46%), giving a risk ratio of 0.61 (95% CI 0.47 to 0.78); the NNT to prevent constipation was 5.5

(95% CI 3.8 to 10).

The authors concluded that the randomized trial literature for effectiveness of transdermal fentanyl

is limited, but it is an important medicine. Most studies recruited fewer than 100 participants and

did not provide data appropriate for meta-analysis. Only a few reported how many patients had

good pain relief but, where data were reported, a majority had no worse than mild pain within a

reasonably short time period.

The evidence pointed to a useful and significant reduction in complaints about constipation for

transdermal fentanyl compared with oral morphine.

Another important paper published in 2012 was a comprehensive review of the literature for

randomized controlled trials (RCTs) of opioids for cancer pain (13). The literature search was done

using PubMed, EMBASE, Cochrane library, clinical trials, national clearing house, Web of

Science, previous narrative systematic reviews, and cross references. The studies were assessed

using the modified Cochrane and Jadad criteria. Analysis of evidence was done utilizing the

modified quality of evidence developed by United States Preventive Services Task Force

(USPSTF). This systematic review of RCTs of opioids for cancer pain showed fair evidence for the

efficacy of transdermal fentanyl and poor evidence for morphine, tramadol, oxycodone, methadone,

and codeine. The evidence was fair based on only one randomized controlled trials.

58

References

1. Raptis E, Vadalouca A, Stavropoulou E, Argyra E, Melemeni A, Siafaka I.Pregabalin vs.

opioids for the treatment of neuropathic cancer pain: a prospective, head-to-head,

randomized, open-label study. Pain Pract. 2014 Jan;14(1):32-42. doi: 10.1111/papr.12045.

2. Reddy A, Yennurajalingam S, Reddy S, Wu J, Liu D, Dev R, Bruera E.The Opioid Rotation

Ratio From Transdermal Fentanyl to "Strong" Opioids in Patients With Cancer Pain. J Pain

Symptom Manage. 2016 Jun;51(6):1040-5. doi: 10.1016/j.jpainsymman.2015.12.312.

3. Reddy A, Tayjasanant S, Haider A, Heung Y, Wu J, Liu D, Yennurajalingam S, Reddy S, de

la Cruz M, Rodriguez EM, Waletich J, Vidal M, Arthur J, Holmes C, Tallie K, Wong A,

Dev R, Williams J, Bruera E.The opioid rotation ratio of strong opioids to transdermal

fentanyl in cancer patients. Cancer. 2016 Jan 1;122(1):149-56. doi: 10.1002/cncr.29688.

4. Matsumura C, Yamada M, Fujihara S, Chisaki Y, Takahashi K, Yano Y.Indication of

Adequate Transdermal Fentanyl Dose in Opioid Switching From Oral Oxycodone in

Patients With Cancer. Am J Hosp Palliat Care. 2016 Mar;33(2):109-14. doi:

10.1177/1049909114554413.

5. Koike K, Terui T, Nagasako T, Horiuchi I, Machino T, Kusakabe T, Hirayama Y, Mihara H,

Yamakage M, Kato J, Nishisato T, Ishitani K.A new once-a-day fentanyl citrate patch

(Fentos Tape) could be a new treatment option in patients with end-of-dose failure using a

72-h transdermal fentanyl matrix patch. Support Care Cancer. 2016 Mar;24(3):1053-9. doi:

10.1007/s00520-015-2880-9.

59

6. Takakuwa O, Oguri T, Maeno K, Yokoyama M, Hijikata H, Uemura T, Ozasa H, Ohkubo

H, Miyazaki M, Niimi A.Analgesic effect of switching from oral opioids to a once-a-day

fentanyl citrate transdermal patch in patients with lung cancer. Am J Hosp Palliat Care.

2013 Nov;30(7):726-9. doi: 10.1177/1049909112470020.

7. Bilen A, Ali A, Alkan I, Altan A.[Comparison of transdermal fentanyl for the management

of cancer pain in adults and elders]. Agri. 2012;24(3):111-6. doi: 10.5505/agri.2012.87528.

Turkish.

8. Othman AH, Mohamad MF, Sayed HA.Transdermal Fentanyl for Cancer Pain Management

in Opioid-Naive Pediatric Cancer Patients. Pain Med. 2016 Feb 25. pii: pnw004. [Epub

ahead of print]

9. Kang JH, Oh SY, Song SY, Lee HY, Kim JH, Lee KE, Lee HR, Hwang IG, Park SH, Kim

WS, Park YS, Park K.The efficacy of low-dose transdermal fentanyl in opioid-naïve cancer

patients with moderate-to-severe pain. Korean J Intern Med. 2015 Jan;30(1):88-95. doi:

10.3904/kjim.2015.30.1.88.

10. Zhu YL, Song GH, Liu DQ, Zhang X, Liu KF, Zang AH, Cheng Y, Cao GC, Liang J, Ma

XZ, Ding X, Wang B, Li WL, Hu ZW, Feng G, Huang JJ, Zheng X, Jiao SC, Wu R, Ren

J.Multicenter clinical study for evaluation of efficacy and safety of transdermal fentanyl

matrix patch in treatment of moderate to severe cancer pain in 474 chinese cancer patients.

Chin J Cancer Res. 2011 Dec;23(4):317-22. doi: 10.1007/s11670-011-0317-7.

60

11. Minami S, Kijima T, Nakatani T, Yamamoto S, Ogata Y, Hirata H, Shiroyama T, Koba T,

Komuta K.Opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix

patch for patients with stable thoracic malignancy-related pain. BMC Palliat Care. 2014 Oct

8;13:46. doi: 10.1186/1472-684X-13-46.

12. Hadley G, Derry S, Moore RA, Wiffen PJ.Transdermal fentanyl for cancer pain. Cochrane

Database Syst Rev. 2013 Oct 5;(10):CD010270. doi: 10.1002/14651858.CD010270.pub2.

Review.


Manchikanti L.A systematic review of randomized trials on the effectiveness of opioids for


61

Toxicity of Transdermal Fentanyl in Clinical Studies.

Figure 2. Consort – like report of Eligible Papers for Toxicity.

62

Summary of data for Toxicity (Table 1, Appendix 4).


conducted.



published in the last five years (Figure 1). The generic search terms (“fentanyl” AND “cancer

pain”) were used. Citation tracking and search for all related eligible articles in PubMed were

performed. We identified 3 eligible paper for toxicity analysis with N=1 observational study and

N=2 case reports/case series.






Observational Studies (Table 2, Appendix 4).

We identified only one observational study about the effects of using transdermal fentanyl (TDF)

on cognitive functions in cancer pain (Table 7).

Analysis of the study was possible with the abstract reading because the paper was written in

Turkish. Fifty patients with cancer pain who had no previous opioid treatments were included in the

study. Pain was evaluated with Visual Analogue Scale (VAS) while, cognitive functions were

assessed using by Addenbrooke's Cognitive Examination final revised version (ACE-R). In

addition, performance was evaluated with Eastern Cooperative Oncology Group Performance

Status (ECOG) and adverse reactions were noted. Patient algological evaluation was done in the

first application and the normal cognitive functions were established using ACE-R. In most cases

63

the treatment began with 25 µg/h TDF and, at certain stages of the treatment, the dose was

increased so that VAS ≤2. ACE-R was applied again on day 30 under sufficient analgesia. All

patients were compared using ACE-R total scores and subgroups (attention-orientation, memory,

fluency, language, visuospatial abilities) at before and after TDF treatment. At the end of the study,

attention-orientation, memory, fluency, language, and ACER total scores showed a statistically

significant improvement after TDF treatment than before. No significant change was obtained for

the visuospatial abilities. No difference was detected in performance status. Author’s conclusion

was that the use of TDF for the treatment of cancer pain is not associated with impairment in

cognitive performance.


Only two papers were indentified on this setting and type of publication (Table 7). Both of them

were published in 2015.

The first paper published by Hemati K et al. (1) report three case reports of severe diarrhea without

most common side effects associated with Fentanyl patches during first 72 h of patient's treatment.

In the 12 h after TDF removal the authors describe the reducing of patient’s diarrhea frequency and

the return of the patient's normal defecation habits. This in an important but not frequent adverse

effect but clinicians must consider this toxicity within the differential diagnosis of diarrhea in

cancer patients.

Second paper reports a case of fentanyl tolerance (2). Opioids are not generally deemed to have an

analgesic ceiling effect on cancer pain. However, there have been occasional reports of tolerance to

opioid development induced by multiple doses of fentanyl. The authors report a case of suspected

tolerance to the analgesic effect of opioid, in which an increasing dose of fentanyl failed to relieve

the patient's cancer pain symptoms, but opioid switching to oxycodone injections enabled a dose

reduction to below the equivalent dose conversion ratio.

64

References

1. Hemati K, Zadeh PR.The Incidence of Severe Diarrhea with Transdermal Fentanyl Patch: An

Uncommon Event. J Clin Diagn Res. 2015 Jun;9(6):UD01-2. doi:

10.7860/JCDR/2015/13194.6024.

2. Sutou I, Nakatani T, Hashimoto T, Saito Y.Fentanyl tolerance in the treatment of cancer pain: a

case of successful opioid switching from fentanyl to oxycodone at a reduced equivalent dose. J

Pain Palliat Care Pharmacother. 2015 Jun;29(2):161-5. doi: 10.3109/15360288.2015.1035832.

65

Clinical considerations on Transdermal Fentanyl

Among opioids, the potent synthetic drug fentanyl citrate is particularly suitable for transdermal

administration, and its utility in pain therapy has been extensively evaluated.

Transdermal fentanyl systems (TTS) are available in five release programs of 12, 25, 50,75, 100

g/h depending on the patch size, and the drug is released continuously for a maximum of 72 hours

(1). When a TTS is removed, fentanyl continues to be absorbed into the systemic circulation from

the cutaneous depot. However, opioid withdrawal symptoms may occur after discontinuation of

TTS administration, as well as after conversion from other opioids to TTS, (2-4).

In stable, chronic, cancer pain this formulation offers an interesting alternative to oral morphine (5-

8). The transdermal route of fentanyl administration is indicated in patients with nausea, vomiting,

problems with swallowing, severe constipation, and poor compliance.

Of course, this formulation is contraindicated during the titration phase, in opioid-naïve patients, or

to control breakthrough pain.

It has become so popular that frequently physicians use transdermal fentanyl as first choice opioid

administration for treating moderate to severe pain (9). In June 2005 an “Important drug warning”

was published by Janssen (10,11). According to this warning “Duragesic ® should only be used in

patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and

who require a total daily dose at least equivalent to Duragesic ® 25 mcg/h. Patients who are

considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of

morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone

daily or an equianalgesic dose of another opioid”.

It was recently emphasized that ensuring adequate opioid tolerance before prescribing a fentanyl

patch is an important way to improve its safe use (12,13). Globally, we con conclude that

transdermal fentanyl represents a good choice for cancer pain management due to the demonstrated

66

efficacy of pain relief and quality of life basing on acceptable level of evidences reported in

literature and analyzed in our report.

67

References

1. Marquard KA, Tharratt RS, Musallam NA. Fentanyl remaining in a transdermal system

following three days of continuos use. Ann Pharmacother 1995; 29: 969-71.

2. Han PKJ, Arnold R, Bond G, Janson D, Abu-Elmagd P and K. Myoclonus secondary to

withdrawal from transdermal fentanyl: a case report and literature review. J Pain Symptom

Manage 2002; 23: 66-72

3. Hunt R. Transdermal fentanyl and the opioid withdrawal syndrome. Palliative Medicine 1996;

10: 347-8

4. 4.Ripamonti C, Campa T, De Conno F. Withdrawal symptoms during chronic transdermal

fentanyl administration managed with oral methadone. J Pain Symptom Manage 2004; 27/3:

191-194

5. Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet Oncol 2001;2:165–72.

6. Menten J, Desmedt M, Lossignol D, Mullie A. Longitudinal followup of TTS-fentanyl use in

patients with cancer-related pain: results of a compassionate-use study with special focus on

elderly patients. Curr Med Res Opin 2002;18:488–98.

7. Radbruch L, Elsner F. Clinical experience with transdermal fentanyl for the treatment of cancer

pain in Germany. Keio J Med 2004;53:23–9.

8. Muijsers RB, Wagstaff AJ. Transdermal fentanyl: an updated review of its pharmacological

properties and therapeutic efficacy in chronic cancer pain control. Drugs 2001;61:2289–307.

9. Ripamonti C, Fagnoni E, Campa T, Brunelli C, De Conno F. Is the use of transdermal fentanyl

inappropriate according to the WHO guidelines and the EAPC recommendations? A study of

cancer patients in Italy. Support Care Cancer 14(5):400-7, 2006

10. Janssen, L.P. Important drug warning.

www.fda.gov/medwatch/SAFETY/2005/duragesic_ddl.pdf

11. FDA Issues Second Safety Warning on Fentanyl Skin Patch.

www.fda.gov/bbs/topics/NEWS/2007/NEW01762.html

http://www.fda.gov/medwatch/SAFETY/2005/duragesic_ddl.pdf

http://www.fda.gov/bbs/topics/NEWS/2007/NEW01762.html

68

12. Friesen KJ, Woelk C, Bugden S. Safety of fentanyl initiation according to past opioid exposure

among patients newly prescribed fentanyl patches. CMAJ 2016 DOI: 10.1503/cmaj.150961

13. Lucyk, S, Nelson L. Consequences of unsafe prescribing of transdermal fentanyl. CMAJ 2016

DOI: 10.1503/cmaj.160291

69

TRAMADOL

Introduction

Tramadol is a synthetic drug with opioid and non-opioid properties. Tramadol consists of two

enantiomers: 1. (+) tramadol and its metabolite (+)-O-desmethyl-tramadol that is agonist of the mu

opioid receptor, and also inhibits serotonin reuptake; 2. (-)-tramadol inhibits norepinephrine

reuptake. These complementary and synergic actions are responsible of tramadol analgesic

properties (1).

Tramadol is rapidly and almost completely absorbed after oral administration but its absolute

bioavailability is only 66%-77% due to first-pass metabolism. After repeated oral administration or

after an intramuscular administration the bioavailability is about 90%–100%, the excretion is

mostly via kidneys (90%) and in the stools (10%). Tramadol is extensively metabolized in the liver

by demethylation, oxidation and conjugation (2-4). O-demethyl-tramadol (M1) is the main active

metabolite, it is catalyzed by cytochrome P450 (CYP) 2D6 and is two to four times more potent

than parent compound. The elimination time of this metabolite is double in patients with hepatic or

renal impairment (3), thus dose adjustment is required in patients with hepatic or renal impairments.

Conversely, poor metabolizers have 14-fold lower concentrations of the active metabolite and may

have less analgesia than expected. Plasma protein binding is ~ 20% and is rapidly distributed in the

body. Peak plasma tramadol levels after oral, rectal, and intramuscular intake are reached in 1-2

hours, 3 hours, and 45 minutes respectively. The drug has a terminal half-life of about 5-6 hours

(5,6). This relatively short half-life results in a required dosage frequency of 4-6 times daily (6).

Extended-release preparations have a longer half-life (10-13.4 hours) and about half peak

concentration after 4 to 6 hours.

With respect to morphine, the potency is considered to be about 1/10 when administrated via

parenteral route and 1/5 when administered orally (10). Other authors found morphine tramadol

ratios ranging from 1:3.8 to 1:5.3 (7-10).

70

Oral tramadol (up to 400 mg/day) is considered effective and safe in the treatment of cancer pain

(7-9). Despite the absence of clear advantages to using tramadol compared to other opioids, it

remains a very used opioid and it is often available in countries where morphine is not. For this

reason it might be considered to be enlisted as an Essential drug by WHO.

71

References

1. Lassen D, Damkier P, Brosen K. The pharmacogenetics of Tramadol. Clin Pharmacokinet 2015;

54: 825-836

2. Gong L, Stamer UM, Tzvetkov MV, Altman RB, Klein TE. PharmGKB summary: tramadol

pathway. Pharmacogenet Genomics 2014; 24:374-380

3. Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F. Concentrations of tramadol

and O-desmethyl-tramadol enantioners in different CYP2D6 genotypes. Clin Pharmacol Ther

2007; 82: 41-47

4. Barbosa J, Faria J, Queiros O, Moreira R, Carvalho F & Dinis-Oliveira RJ. Comparative

metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metabolism Reviews

2016; 48/4: 577-592

5. Lintz W, Barth H, Osterloh G, Schmidt-Bothelt E. Bioavailability of enteral tramadol

formulations. 1st communication: capsules. Arzneimittelforschung 1986; 36:1278-1283

6. Raber M, Schulz HU, Schurer M, Bias-Imhoff U, Momberger H. Pharmacokinetic properties of

tramadol sustained release capsules: 2nd communication: investigation on relative availability

and food interaction. Arzneimittelforschung 1999; 49:588-593

7. Osipova NA, Novikov GA, Beresnev VA, Loseva A. Analgesic effect of tramadol in cancer

patients with chronic pain: a comparison with prolonged-action morphine sulfate. Curr Ther Res

1991; 50:812–21

8. Tawfik MO, Elborolossy K, Nasr F. Tramadol hydrochloride in the relief of cancer pain: a

double blind comparison against sustained release morphine. Pain (Suppl) 1990; 5:377.

9. Wilder-Smith CH, Schimke J, Osterwalder B, Senn HJ. Oral tramadol, a mu-opioid agonist and

monoamine reuptake-blocker, and morphine for strong cancer-related pain. Ann Oncol 1994;

5:141–6

10. Hennies HH, Friderichs E, Schneider J. Receptor binding, analgesic and antitussive potency of

tramadol and other selected opioids. Arzneimittelforschung 1988; 38:877–80

72

Efficacy of Tramadol in Clinical Studies

Figure 1. Consort-Like diagram of selected papers for efficacy.

73



conducted.



published in the last five years (Figure 1). The generic search terms ("tramadol" AND "cancer

pain") were used. Citation tracking and search for all related eligible articles in PubMed were

performed. We identified only 4 eligible paper for efficacy analysis with N=3 Randomized

Controlled Trials, N=1 Review, N=1 prospective open label studies. We did not find retrospective

studies or case reports/case series. Major percentage of last 5 years evidences came from

randomized trials. One trial was identified with cross-references analysis.






http://www.cebm.net/index.aspx?o=5653

74

Randomized Controlled Trials (Table 2, Appendix 5).

In the last five years literature search, three randomized controlled trials were identified.

The most important study was published by Bandieri et al. on the Journal of Clinical Oncology (1)

in 2016 and analyzed the efficacy of low dose morphine versus weak opioids such as tramadol

alone or in combinations with paracetamol, or codeine in fixed combination with Paracetamol. The

study was conducted among 240 Italian cancer patients randomly assigned to receive either low-

dose oral morphine (M) or a weak opioid (WO) from randomization until day 28. The primary

outcome occurred in 88.2% of the low-dose morphine and in57.7% of the weak-opioid group (odds

risk, 6.18; 95% CI, 3.12 to 12.24;P.001). The percentage of responder patients was higher in the

low-dose morphine group, as early as at 1 week. This study does not support the use of tramadol

versus low dose morphine but represents a simplified approach to increase patient access to strong

(and low cost) opioids at an earlier stage in the disease trajectory, improving overall pain control.

The second one was published in 2016 by Kress HG et al. (2) but after full-text reading we cannot

consider this paper for our report for two reasons: the study regards the opioid conversion rates

from tramadol to tapentadol prolonged release and this is not the objective of our revision.

Moreover, it is a post hoc subgroup analysis of a randomized-withdrawal, active- and placebo-

controlled, double blind phase 3 study.

The last study was published by Bilen A et al in 2013 (3) analyzed the efficacy of tramadol as co-

analgesic in cancer patients using trans-dermal fentanyl (TDF) in 50 cancer patients. Study was

positive for the main objective and when TDF and tramadol are used together, TDF need is reduced

and patients better tolerate the pain management protocol.

75

Systematic Review (Table 3, Appendix 5).

Only one systematic review was identified by our search.

The study was published in 2012 (4) and it’s comprehensive review of the literature for randomized

controlled trials (RCTs) of opioids for cancer pain. The literature search was done using PubMed,

EMBASE, Cochrane library, clinical trials, national clearing house, Web of Science, previous

narrative systematic reviews, and cross references. The studies were assessed using the modified

Cochrane and Jadad criteria. Analysis of evidence was done utilizing the modified quality of

evidence developed by United States Preventive Services Task Force (USPSTF). This systematic

review of RCTs of opioids for cancer pain showed fair evidence for the efficacy of transdermal

fentanyl and poor evidence for morphine, tramadol, oxycodone, methadone, and codeine. For

tramadol, there were 3 trials evaluating tramadol. One trial evaluated the influence of tramadol on

the dose escalation of transdermal fentanyl. One study evaluated tramadol to placebo for

neuropathic cancer pain. The third study evaluated tramadol compared to morphine in 20 patients in

each group.

The evidence was poor based on 3 low quality studies (this study was analyzed also for trans-

dermal fentanyl report).

76

Prospective Open Label Study (Table 4, Appendix 5).

Only one Prospective Open Label Study was identified by our search. The objective of the study

published on 2015 (5) was to determine the efficacy of a fixed combination of tramadol and

paracetamol (acetaminophen) in the treatment of pain in 353 advanced cancer patients.

The average duration of treatment with a fixed combination tramadol and acetaminophen was 57

days (13-330 days). Already after 24 hours of treatment the average pain score was significantly

lower (p<0.0001) compared to the admission day [5.00 (4:00 to 8:00) during the first days versus

2.00 (1:00 to 7:00) during the second day of treatment]. The average dose of the fixed combination

tramadol and acetaminophen tablets was 4.8 ± 1.8 (180 mg of tramadol and 1560 mg paracetamol).

Side effects, in the treatment of pain with a fixed combination tramadol and acetaminophen, were

found in 29.18% of patients, with a predominance of nausea and vomiting.

77

References

1. Bandieri E, Romero M, Ripamonti CI, Artioli F, Sichetti D, Fanizza C, Santini D, Cavanna L,

Melotti B, Conte PF, Roila F, Cascinu S, Bruera E, Tognoni G, Luppi M. Randomized Trial of

Low-Dose Morphine Versus Weak Opioids in Moderate Cancer Pain. J Clin Oncol. 2016 Feb

10;34(5):436-42. doi: 10.1200/JCO.2015.61.0733.

2. Kress HG, Koch ED, Kosturski H, Steup A, Karcher K, Dogan C, Etropolski M, Eerdekens

M.Direct conversion from tramadol to tapentadol prolonged release for moderate to severe,

chronic malignant tumour-related pain. Eur J Pain. 2016 Oct;20(9):1513-8. doi:

10.1002/ejp.875.

3. Bilen A, Ali A, Baturay F, Ozcan B, Altan A.[Concomitant use of strong and weak opioids in

the management of chronic cancer pain]. Agri. 2013;25(1):7-12. doi: 10.5505/agri.2013.60252.

Turkish.


Manchikanti L.A systematic review of randomized trials on the effectiveness of opioids for


5. Husic S, Izic S, Matic S, Sukalo A. Efficacy and safety of a fixed combination of tramadol and

paracetamol (acetaminophen) as pain therapy within palliative medicine. Mater Sociomed. 2015

Feb;27(1):42-7. doi: 10.5455/msm.2014.27.42-47.

78

Toxicity of Tramadol in clinical studies.

Figure 1. Consort-Like diagram of selected papers for Toxicities.


conducted.



published in the last five years (Figure 1). The generic search terms ("tramadol" AND "cancer

pain") were used. Citation tracking and search for all related eligible articles in PubMed were

performed. We identified only 2 eligible paper for toxicities analysis with N=2 case reports/case

series.

79


Only two papers were indentified on this setting and type of publication (Table 5). Both of them

were published in 2015.

First paper was published by Kurten C et al. (1) and reports about a 79-year-old non-diabetic patient

admitted to the emergency room with severe hypoglycemia after 50 mg of tramadol tablet for

headache. As already in retrospective studies (Level of Evidence 3) reported for methadone (2)

mechanisms and the risk factors for this potential side effect remain unclear. We consider this paper

of adverse effect in non-cancer patients due to the potential class- metabolic toxicities of opioids

and their management. Article was in German.

The second paper (3) considers another little known adverse effect from opioids (seizures) in a

laryngeal cancer patient on treatment with tramadol. Some reports have found that tramadol triggers

seizure activity at high doses, whereas a few preclinical studies have found that this seizure activity

is not dose-related. After tramadol was stopped, patient symptoms quickly improved.

There are many reports of seizures following tramadol overdoses, including seizures associated

with intravenous tramadol as premedication, seizures in drug abusers, and seizures in association

with tramadol intoxication. In all of these cases, high blood tramadol concentrations likely induced

the seizure activity. However, the relationship between the tramadol dose and seizure activity

remain controversial.

80

References

1. Kürten C, Tzvetkov M, Ellenrieder V, Schwörer H.[Severe hypoglycemia following tramadol

intake in a 79 year old non-diabetic patient]. Dtsch Med Wochenschr. 2016 Sep;141(20):1480-

1482. German.

2. Moryl N, Pope J, Obbens E. Hypoglycemia during rapid methadone dose escalation. J Opioid

Manag. 2013 Jan-Feb;9(1):29-34. doi: 10.5055/jom.2013.0144.

3. Beyaz SG, Sonbahar T, Bayar F, Erdem AF.Seizures associated with low-dose tramadol for

chronic pain treatment. Anesth Essays Res. 2016 May-Aug;10(2):376-8. doi: 10.4103/0259-

1162.177181.

81

Adverse effects of tramadol

Although tramadol is considered to be a drug at low risk of causing respiratory depression, two

cases of severe respiratory depression after tramadol use have been described in children (1) and in

one adult with cancer pain and renal insufficiency (2).

Case report of hyponatremia may occur during tramadol treatment (3-5). Natremia must be

measured when neurological abnormality occurs with tramadol treatment.

Withdrawal syndrome may occasionally present during tramadol treatment (6,7).

Seizures have been reported with tramadol at normal doses (8), so the drug should be avoided in

patients with epilepsy.

A severe serotonin syndrome may occur when tramadol is combined with drugs that increase

serotonin activity such as monoamine oxidase inhibitors (MAOIs) (9).

Although tramadol is thought to have low abuse and dependence potentials worldwide, its abuse

has become a serious problem in many countries, particularly in the Middle East, Africa, and West

Asia (10).

There is evidence that the incidence rate for abuse of tramadol is 69/1,000 persons per year and the

dependence rate is 6.9/1,000 persons per year (11).

82

References

1. Lee CR, McTavish D, Sorkin EM. Tramadol. Drugs 1993; 46:313–40

2. Barnung SK, Treschow M, Borgbjerg FM. Respiratory depression following oral tramadol in a

patient with impaired renal function. Pain 1997 ; 71:111–2

3. Le Berre JP, Desrame J, Lecoules S, Coutant G, Bechade D, Algayres JP. Hyponatremia due to

tramadol. Rev Med Interne Jun 27; [Epub ahead of print], 2007

4. Udy A, Deacy N, Barnes D, Sigston P. Tramadol-induced hyponatraemia following

unicompartmental knee replacement surgery. Anaesthesia 2005; 60(8):814-6

5. Hunter R. Tramadol and hyponatraemia. Aust Prescr 2004; 27:97

6. Ripamonti C, Fagnoni E, De Conno F. Withdrawal syndrome after delayed tramadol intake. Am

J Psychiatry 2004; 161(12):2326-7

7. Rodriguez Villamanan JC, Albaladejo Blanco C, Sanchez Sanchez A, Carvajal A, Martin Arias

L, Garcia del Pozo J. Withdrawal syndrome after long-term treatment with tramadol. Br J Gen

Pract. 2000; 50(454):406

8. Kaye K. Trouble with tramadol. Austr Prescr 2004; 27 :26-7

9. Park SH, Wackernah RC, Stimmel GL. Serotonin Syndrome: is it a reason to avoid the use of

tramadol with antidepressants?. J of Pharmacy Practice 2014; 27/1:71-78

10. United Nations. International Narcotics Control Board 2013. Report of the International

Narcotics Control Board for 2013. New York: United Nations. Available from:

http://www.incb.org/documents/Publications/annualReports/AR2013/English/Global_developm

ents__inthe_non-medical_use_of_tramadol.pdf. Accessed July 10,2015

11. Knisely JS, Campbell ED, Dawson KS, Schnoll SH. Tramadol postmarketing surveillance in

health care professionals. Drug Alcohol Depend 2002; 68: 15-22.

83

Clinical Role of Tramadol

Tramadol is considered a “weak” opioid because of its ceiling effect for which more than a certain

threshold of dose cannot increase the effectiveness of the drug but only influence the appearance of

side effects. Unlike the role of “strong” opioids, which is universally recognized in the treatment of

moderate to severe pain, there is no common agreement regarding the role of tramadol and others

“weak” opioids for mild to moderate pain. Controversial points regarding the use of second step are

that (1) there are insufficient data regarding the effectiveness and toxicities of the so called “weak”

opioids; (2) both codeine and tramadol may be less analgesic in poor metabolizers; (3) the second-

step drugs are often marketed in combination with a non-opioid such as paracetamol, aspirin, or

NSAID and it is the latter component that limits the dose; and (4) these drugs are often expensive in

respect to their potential benefits (cost–benefit ratio). Various authors have debated the role and the

utility of the second step of the WHO analgesic ladder.

Several authors have suggested abolishing the second step and initiating earlier low-dose morphine

therapy. In routine clinical practice, the question that arises is what really changes regarding the

analgesia and tolerability of weak opioids, or low-dose strong opioids, if one or the other is used

even for mild–moderate pain? Low dose oral morphine is a reliable treatment in opioid-naïve

advanced cancer patients (1-3).

Basing on the quality of all analyzed studies and the strength of evidence, we can conclude that the

evidence about the use of tramadol remains poor. However, this may be explained with the low

number of studies in the last five years in this particular setting.

We have to consider that oral tramadol is present also in countries where oral morphine is not

present or in countries where there are several restrictions in using morphine (oral or parenteral) so

to prevent proper pain treatment.

In these situations tramadol may have a particular role if we consider the right dosage (up to 400

mg/day) and pay attention to the adverse effects in particular in patients with renal impairment (4).

84

References

1. Bandieri E, Romero M, Ripamonti CI, Artioli F, Sichetti D, Fanizza C,. Randomized Trial of

Low-Dose Morphine Versus Weak Opioids in Moderate Cancer Pain. J Clin Oncol. 2016 Feb 10;

34(5): 436-42

2. Maltoni M, Scarpi E, Modonesi C, et al. A validation study of the WHO analgesic ladder: a two-

step vs three-step strategy. Support Care Cancer 2005;13:888–94.

3. Mercadante S, Porzio G, Ferrera P, et al. Low morphine doses in opioid-naive cancer patients

with pain. J Pain Symptom Manage 2006;31:242–7.

4. Sande TA, Laird BJ, Fallon MT. The use of opioids in cancer patients with renal impairment-a

systematic review Support Care Cancer. 2016 Oct 15. [Epub ahead of print] Review.

eml opioids for cancer pain: a comparative … · pain is a frequent and impacting symptom not only...

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