Pain management

Hozan Jaza

MSc. Clinical Pharmacy

College of Pharmacy

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Definition

• PAIN is an unpleasant sensory and emotional experience associated with actual and potential tissue damage, or described in terms of such damage.

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Neuroanatomy of pain transmission

• The majority of tissues and organs are innervated by special sensory receptors ( nociceptors) connected to primary afferent nerve fibers of differing diameters.

• Small myelinated A fibers and unmyelinated C fibers are responsible for the transmission of painful stimuli to the spinal cord where these afferent primary fibers terminate in the dorsal horn.

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• The most important parts of this process are the wide dynamic range cells in the spinothalamic tract that project to the thalamus and to the somatosensory cortex beyond.

• Modulation or inhibition of these neurones within the spinal cord result in less activity in the pain pathway.

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Neurotransmitters and pain

• Various neurotransmitters in the dorsal horn of the spinal cord are involved in pain modulation.

• These include amino acids such as glutamate and γ-aminobutyric acid (GABA), monoamines such as noradrenaline and 5-hydroxytryptamine (5-HT, serotonin) and endogenous opioid.

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Assessment of pain

• Evaluation of pain should include a detailed description of the pain & an assessment of its consequence.

• There should be a full history, psychosocial assessment, medication history & assessment of previous pain problems & any factors that affect the pain.

• Diagnostic laboratory tests, imaging, including plain radiography, computer tomography ( CT) and magnetic resonance imaging (MRI), and various imaging techniques, and diagnostic nerve blocks may aid confirmation of the diagnosis.

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• Pain is subjective phenomenon & quantitative assessment is difficult.

• The most commonly used instruments are visual analogue & verbal rating scales.

• Visual analogue scales are 10 cm long lines labelled with an extreme at each end, usually “no pain at all '' and ''worst pain imaginable ''.

• The patient is required to mark the severity of the pain between the two extremes of the scale as: None, mild, moderate & severe.

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Management

• Acute pain results from noxious stimulation, such as injury. It can be managed by analgesic drugs & is often self limiting.

• Chronic pain can be defined as pain which has lasted for 6 months or more.

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Analgesic ladder:

There are 3 steps:

1- Non-opioids analgesics (Aspirin, NSAID, Paracetamol ± adjuvant)

2- Weak opioids (Codeine, Dextropropoxyphene, Dihydrocodeine, Tramadol, ± adjuvant).

3- Strong opioids ( Morphine, Hydromorphone, Methadone, Fentanyl, Oxycodone, ± adjuvant) .

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• The analgesic efficacy of non- opioids such as NSAID, aspirin & paracetamol is limited by SE & ceiling effects.

• If pain remains uncontrolled, then a weak opioid, such as codeine or dihydrocodeine may be helpful. There may be additional benefit in combining a week opioid with a non- opioid drug, although many commercial preparation contain inadequate quantities of both components & are no more effective than non- opioid alone.

• Strong opioids, of which morphine is the gold standard, have no ceiling effect & therefore increased dosage gives increased analgesic.

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Analgesic drugs:

Paracetamol

• It is available as an ( OTC) and is a component of many cold and influenza remedies.

• Compared with other analgesics, paracetamol is not as a potent but when taken in combination with a NSAID or opioid, there is an additive analgesic effect.

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Non- steroidal anti- inflammatory drugs: • Produce their effect through cyclo- oxygenase inhibition,

widely used to relieve pain, with or without inflammation in people with acute & chronic musclo- skeletal disorder.

• In single doses, NSAIDs have superior analgesic activity compared to paracetamol.

• In higher doses they have both analgesic & anti- inflammatory effects, which makes them particular useful for the treatment of continuous or regular pain associated with inflammation.

• NSAIDs have been show to be suitable for relief of pain in dysmenorrhea, toothache & some headaches, secondary bone tumors. 14

Cox-2 selective drugs: • Cox-1 & cox-2 • Cox-1 is a constitutive enzyme that exist in a variety of

tissue where it catalyses the formation of essential prostaglandin. It doesn’t have a role in nociception or inflammation.

• Cox-2 is an inducible enzyme that appears in damaged tissues shortly after injury & leads to the formation of inflammatory prostaglandins within there tissues. In practice use of Cox-2 specific drugs is associated with reduced risk of GI side effect when compared with non- selective drugs, but have cardio toxicity.

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Weak opioids: • These drugs are prescribed by primary care physicians, either

alone or in combination with other analgesic for a wide variety of painful disorders. There are 3 major drugs in this group:

• Codeine, dihydrocodeine & dextropropoxyphene. All used for pain that is not responsive to non- opioid analgesic.

Codeine: • It is suggested as the 1st choice drug in this group . It is

structurally similar to morphine and about 10% of the codeine is demethylated to form morphine . In combination with NSAIDs , the analgesic effects are usually additive.

• It is a powerful cough suppressant as well as being very constipating.

• Duration of codeine as analgesic is 3 hrs.

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Dihydrocodeine:

• Chemically related to codeine, has similar properties to codeine when used at the same dosage & slightly more potent.

Dextropropoxyphene:

• Prescribed in combination with other analgesics, such as paracetamol.

• Some references indicate that the analgesic efficacy of this drug is less than aspirin or paracetamol.

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Strong opioids:

Morphine:

• It is the gold standard of strong opioid analgesic. • It is available as oral, rectal& injectable formulation and

has a duration of action of about 4 hrs after oral administration. There is no ceiling effect when the dose is increased.

• For rapid control of acute pain an i.v. bolus dose of 2-5 mg titrated against relief of the patient's pain.

• For control of chronic pain or pain arising from malignancy, an oral regimen is appropriate using a quick- release formulation of morphine, after control of pain is achieved, it is usual to change to an oral modified release formulation.

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Other strong opioids:

• Opioids such as pethidine and dextromoramide offer little advantage over morphine in that they are weaker in action with short duration of action 2hr).

• Dipipanone contain an antiemetic cyclizine in its combination, and increasing doses lead to sedation and the risk of developing a tardive dyskinesia with long term use.

• Methadone has long elimination half life of 15-25 hr & accumulation may occur in early stage of use.

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• Hydromorphone & oxycodone are synthetic opioids.

• Some patients appear to tolerated hydromorphone & oxycodone better than morphine.

• Fentanyl is now available as a transdermal patch for long term use. The patch is designed to release the drug continuously for 3 days. Patches should replace every 72 hrs.

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Agonist- antagonist & partial agonists:

Pentazocine:

• Is a benzomorphan that is an agonist & at the same time a very weak antagonist at the M receptor, has short duration of action 3hr.

Tramadol:

• It is centrally acting analgesic that has opioid agonist activity and also has antidepressant activity.

• It is not as potent as morphine, & efficacy is limited by side effects, including drowsiness , nausea and vomiting.

• its value in management of neuropathic pain and it is acceptable alternative to the weak opioids.

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Buprenorphine

• It is a semi-synthetic, highly lipophilic opioid that is a partial agonist at the m receptor and an antagonist at both the delta and k receptor.

• It undergoes extensive metabolism when administered orally and to avoid this effect, it is given sublingually.

• It is use in the management of chronic pain.

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Adverse effects of opioids

• The adverse effects of opioids are nearly all dose

related, and tolerance develops to the majority with long-term use.

Respiratory depression

Sedation

Nausea and vomiting

Constipation

Tolerance, dependence and addiction

Urinary retention

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Special techniques of opioid drug delivery

Epidural analgesia:

• Epidural injections and infusions may be effective in relieving pain arising from both malignant & non- malignant disease.

• They are very effective in post operative & labor pain.

• Various combinations of local anesthetics, opioids or steroids can be introduced into the epidural space to the level of the pain.

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Epidural opioids:

• Effective analgesia can be obtained by administering small doses of opioids to the epidural space, because there are opioid receptors in the spinal cord.

• They can be given with & without long acting local anesthetic drugs.

• Severe respiratory depression, N&V, urinary retention & pruritis can occur after their use.

• Life- threatening respiratory depression can occur when additional opioids are given by other routes to patient already receiving epidural opioids.

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Epidural local anesthetics:

• Long- acting local anesthetic drugs such as bupivacaine are effective in relieving pain after major surgery.

• Analgesia here can be obtained in deep internal organs by blocking nerves in the spinal canal by this way it serve both superficial & deep tissues.

• Adverse effects include hypotension , muscle weakness in the area supplied by nerve and rarely infection and haematomas.

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Local anesthetic : • Local anesthetic drugs, such as lidocaine & bupivacaine,

injected close to a sensory nerve will block the conduction of nerve impulses and provide excellent analgesia.

• Some local anaesthetics are given with adrenaline (epinephrine) to reduce systemic toxicity & increase the duration of action.

• Local anesthetic can be applied directly to wounds or by local infiltration to produce post operative analgesia but will not block pain arising from deep internal organs.

• Permanent neural blockade for control cancer pain may be achieved by using a neurolytic agent such as absolute alcohol or phenol.

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Adjuvant medication:

• In some types of pain, such as pain of cancer or neuropathic pain, the addition of non – analgesic drugs to analgesic therapy can enhance pain relief. Examples are:

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Drug class Type of pain Example

Anti-epileptics Neuropathic pain Migraine Cluster headache Trigeminal neuralgia postherpetic neuralgia amputation

Carbamazepine Sodium valproate Gabapentin Pregabalin Lamotrigine

Antidepressants Neuropathic pain Musculoskeletal pain facial pain low back pain

Amitriptyline Imipramine Venlafaxine Duloxetine

Intravenous anaesthetic agents

Neuropathic pain Burn pain Cancer pain

Ketamine

Skeletal muscle relaxants

Muscle spasm Spasticity

Baclofen Dantrolene Botulinum toxin (type A)

Steroids Raised intracranial pressure Nerve compression

Dexamethasone Prednisolone 29

Drug class

Type of pain

Example

Antibiotics

infection As indicated by culture and sensitivity

Antispasmodics Colic Smooth muscle spasm

Hyoscine butylbromide Loperamide

Hormones/ hormonal analogues

Malignant bone pain Spinal stenosis Intestinal obstruction

Calcitonin Octreotide

Bisphosphonates Bone pain (caused by cancer or osteoporosis)

Pamidronate (for cancer pain) Alendronate

Benzodiazepines acute muscle spasm neuropathic pain

Diazepam Clonazepem

Antihistamines muscle spasm tension headache cancer pain

Hydroxyzine

Alpha2-adrenergic agonist muscle spasm

Tizanidine Clonidine

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Stimulation- produced analgesia:

Stimulation- produced analgesia can be used for trauma, post operative pain, labour pain and various chronic pain.

transcutaneous electrical nerve stimulation (TENS)& acupuncture:

Transcutaneous electrical nerve stimulation (TENS)

• TENS machines are portable battery- powered devices that generate a small current to electrodes applied to the skin.

• The electrodes are placed at the painful site or close to the peripheral nerve innervating the painful area & the current is increased until paraesthesia is felt at the site of pain.

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• Acupuncture stimulate endogenous opioids. Acupuncture has been recommended for the treatment of low back pain.

Treatment of selected pain syndromes:

Postoperative pain: • The majority of patients suffer pain following surgery.

• The site & nature of surgery affect the severity of pain.

• It is now common to treat postoperative pain with combination of paracetamol , NSAIDs , opioids & local anesthetic blocks or wound infiltration.

Cancer pain : • Pain here may arise from different sources & may be acute

& chronic pain.

• Pain can be treated both with drug & other techniques such as radiotherapy & nerve blocks.

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Opioid use in cancer pain:

• Morphine is the 1st line opioid, if not tolerated, alternatives such as oxycodone or hydromorphone both having long half lives.

• Methadone may be useful when alternatives of morphine have failed or the patient has experienced intolerable adverse effect.

• When oral route is not available, other routes of administration such as buccal, rectal, transdermal, parenteral or spinal routes may be considered.

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Use of adjuvant drugs in cancer pain:

• Neuropathic pain is common in cancer.

• TCA & anticonvulsant should used early, but where these are ineffective ketamine can be used.

• Levomepromazine is a phenothiazine with analgesic activity, is a useful alternative when opioid cannot be tolerated.

• Corticosteroid are useful in managing acute & chronic cancer pain, & is useful for raised intracranial pressure or relieving pressure caused by tumors on the spinal cord and in the brain.

• Dexamethasone is the most commonly used corticosteroid to ameliorate raised intracranial pressure in patients with brain tumors .

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Specific neuropathic pain syndromes

Post-herpetic neuralgia • The pain associated with herpes zoster infection is severe,

continuous & often described as burning and lancinating. • Antiviral therapy such as acyclovir initiated at the 1st sign of

the rash can reduce the duration of pain, particularly post herpetic pain, which follows disappearance of the rash.

• TCA such as amitriptyline are the mainstay of treatment. They may be combined with anticonvulsant if the response is poor or incomplete.

• Carbamazepine is historically important but newer anti-epileptic drugs, such as gabapentin and pregabalin, are considered first line therapy and may be better tolerated .

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Diabetic peripheral polyneuropathy

• Nerve damage and neuropathy is one of the long-term complications of diabetes mellitus and is most prevalent in elderly patients with type2 diabetes.

• Patients describe numbness but also experience a burning sensation on their feet. The sensory loss can result in painless foot ulcers.

• TCA and anti-epileptics such as gabapentin and pregabalin, have been demonstrated to be beneficial.

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Trigeminal neuralgia:

• It presents as abrupt, intense bursts of severe, lancinating pain, provoked by touching sensitive trigger areas on one side of the face.

• Anticonvulsants particularly carbamazepine, have been used.

• If drug therapy is ineffective surgical technique is needed.

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Post amputation & phantom limb pain:

• Pain will be present in the immediate post operative period in the stump, this may be caused by muscle spasm, nerve injury & sensitivity of the wound & surrounding skin.

• As the wound heals, the pain should subside.

• TCA may be helpful for stump pain, and surgery may be necessary to restore vascular supply or reduce trauma to nerve ending.

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• Phantom pain is a referred pain which produces a burning sensation ,felt in the absent limb.

• The patient with phantom limb pain is often anxious, depressed & frightened, all of which exacerbate pain.

• Analgesic drugs alone are generally not enough for phantom pain, but TCAs & anticonvulsant are adjuvants.

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Dysmenorrhea: • It is a common cause of pelvic pain in women. • NSAIDs are effective as first line therapy due to their

effect on cyclo- oxygenase inhibition but it can be managed by oral contraceptive.

• Dysmenorrhea due to endometriosis may require androgenic drug like Danazol.

Burn pain: • Patient with burn require painful procedures such as

physiotherapy , debridement & skin grafting. • Premedication with a strong opioid before the

procedure. • The anesthetic drug ketamine has potent analgesic

activity & used to reduce the pain of dressing changes.

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Back pain

• The most practical classification is based on the duration of symptoms.

• Acute low pain is generally defined as pain that lasts for a few days or weeks. The majority of these problems tend to be self-limiting and resolve spontaneously. Typically treatments include rest, adequate analgesia with paracetamol, combined with a NSAID and/ or a weak opioid, and physiotherapy.

• Chronic back pain lasts for much longer and progressively leads to a chronic state associated with pain, depression, anxiety and disability.

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