TRANSDERMAL APPROACH TO PAIN RELIEF: PRESENT AND FUTURE

S K MALHOTRADepartment of Anesthesia and Intensive Care

Postgraduate Institute of Medical Education and Research, Chandigarh, INDIA

Transdermal drug delivery:

- Defined as the “non-invasive delivery of medications through the skin surface”

- Patches deliver an analgesic drug - - at a predetermined rate across the dermis - to achieve either a local or systemic effect

- Analgesics as a 'pain relief patch' → gaining popularity

TDD: not a new concept

- Homemade medicinal preparations – date back to 20th century

- Mustard plasters: used for severe chest congestion

- Belladonna Plaster ( 0.25%) : in US pharmacopeia (Scheindlin , 2004)

Scheindlin S. Transdermal drug delivery: past, present, future. Mol Interven 2004; 4: 308–12.

• Success of nicotine patches: - two decades ago → revolutionized the use of TDD

• During last decade: - increasing number of analgesic drugs - - available as transdermal patches

Advantages of patches: over conventional parenteral / oral routes

• Controlled absorption - more uniform plasma concentrations

• Bioavailability improved - by avoiding : - First-pass hepatic metabolism - Enzymatic or pH-associated deactivation

• Simple and painless application

Advantages ……contd

• Flexibility in terminating drug administration - by patch removal

• Patient compliance improved - patches are simple, non-invasive, convenient

• Clear labelling - ensures rapid identification of medication

Limitations : Transdermal Drug Delivery (TDD)

• Local irritation or sensitization of skin

• Not all drugs suitable - for transdermal delivery

• Not suitable for shocked patients ( decreased periph. blood flow → unreliable absorption )

• Relatively more expensive - in comparison with other routes

Pharmacokinetics

• Drug should be in a high conc. within the patch - for transdermal delivery to occur

• Energy for drug release derived from - ‘concentration gradient’ - Existing between a saturated soln. of drug in TDD System and much

lower conc. in skin

- Drug movement occurs by diffusion → maintaining a constant diffusion and conc. of drug in

circulation

Pharmacokinetics………contd

Rate of permeation across the skin is given by:

- D : diffusion coefficient - Co: constant concentration of drug in the patch - P : partition coefficient between skin and bathing solution - h : thickness of the skin

Factors improving Transdermal permeation

• Molecular weight < 500 Da

• Affinity for both lipophilic and hydrophilic phases:

( extreme partitioning not conducive to successful drug delivery via skin)

• Low melting (affects the release of drug)

• Non-ionic

• High potency (effective at low dosage)

• Short half-life

Components - of a Transdermal Delivery System

Components of the reservoir and matrix patches

Main Components

• Release liner: protects patch during storage - removed before its use

• Drug: drug solution - in direct contact with release liner

• Adhesive: - adheres components of patch together - sticks patch to the skin

• Membrane: controls release of drug from reservoir and multi-layer patches

• Backing laminates: protects patch from environment

• Permeation enhancers

Types of transdermal patches

• Single-layer drug-in-adhesive patch

• Multi-layer drug-in-adhesive patch

• Reservoir patch

• Matrix patch

Single-layer drug-in-adhesive patch:

• Adhesive layer adheres the various layers together & - sticks the system to the skin

• Also responsible for releasing the drug

Multi-layer drug-in-adhesive patch:

• Both adhesive layers are responsible for release of the drug

• One layer is for immediate release - other layer controls release of the drug from a reservoir

Reservoir patch:

• Has a separate drug layer as a liquid compartment, containing a drug solution (between a backing layer and a rate-controlling membrane)

• This results in a zero-order rate of release

• Reservoir patches should not be cut

Matrix patch:

• Has a drug layer of a semi-solid matrix containing a drug soln. or suspension • dispersed within a polymer pad in direct contact with the skin

• Adhesive layer surrounds the drug layer

Application of Transdermal Delivery Systems

Acute Pain:

• Transdermal analgesics : being used in many areas of pain management

• Two roles in acute pain management - prevention and treatment

• Local anaesthetic patch : - prevent the pain of venesection or vaccination

• Particularly useful in paediatric practice

Acute Pain….contd

• NSAIDs patch : for acute pain from musculoskeletal injury

• Opioids patches: in use for many years - but not recommended for acute pain due to - delayed onset of action and risks of toxicity

• Fentanyl patient-controlled transdermal system: - Advantages of PCA (patient-controlled analgesia) - with a transdermal delivery system - Uses iontophoretic mechanism - to speed up drug delivery

Chronic Pain

• Transdermal analgesics: useful for chronic nociceptive pain

• Fentanyl and buprenorphine: available for many years in patch form

• Capsaicin and lidocaine patches: - helpful in chronic neuropathic pain

Analgesic patches - currently available in UK

• Diclofenac ((Voltrol)

• Fentanyl

• Buprenorphine

• EMLA

• Lidocaine + Tetracaine plaster (Rapydan)

• Tetracaine (Ametop)

• Lidocaine 5% (Versatis)

NSAID patches:

Diclofenacepolamine 1% (Voltarol gel patch )

• Licensed for pain in - epicondylitis and ankle sprain

• NSAIDs penetrate subcutaneous tissues - accumulate under the site of patch • Reduction in pain scores - after 3 hr (in ankle sprains) • After patch removal, plasma diclofenac half-life → 9–12 h ( 1–2 h after oral intake )

Diclofenac patch….contd

• Systemic transfer after removal -- 2% (side-effects rare )

• No GI bleeding, ulcers, or cutaneous events reported

• In knee osteoarthritis – patch as effective as oral diclofenac ( Banning 2008)

• Side effects: pruritis, erythema, rashes

Banning M. Topical diclofenac: clinical effectiveness and current uses in osteoarthritis of the knee and soft tissue injuries. Exp Opin Pharmacother 2008; 9: 2921–9

Opioid patches

• Fentanyl (µ-agonist)

• Buprenorphine (partial µ-agonist )

→ high lipid solubility -- suitable as patch

Fentanyl patches:

• Licensed for malignant and non-cancer pain

• Matrix design (eg ‘Fentalis’ )

• Reservoir design ( eg ‘Mezolar’ )

• ‘Durogesic D-Trans’ (adhesive matrix containing dissolved Fentanyl)

Fentanyl…..contd

• Constant plasma fentanyl conc. - for 72 h application ( max. plasma conc. between 12 -24 h)

• Blood flow and anatomical site of patch – no effect on drug

• Increase in body temp. - increases fentanyl delivery by 30 %

Fentanyl…..contd

• Slow increase in initial fentanyl plasma conc. → evaluate analgesic efficacy after 24 h ( other analgesia required during initial period)

• Delay is due to - formation of a fentanyl depot within the skin layers

• After patch removal - fentanyl eliminated slowly due to depot collection

• Elimination can be delayed – by co-administration of ketoconazole, verapamil, diltiazem, and amiodarone

Fentanyl…..contd

• Patches are prescribed - - based on number of µg/hr of drug released

• MHRA (Medicines and Healthcare products Regulatory Agency) :

“Fentanyl patches should only to be used in patients who have previously tolerated opioids” (due to the risk of ventilatory depression)

- Must inform patients /caregivers of their safe use and side-effects

MHRA and CHM. Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure and inappropriate use. Drug Saf Update 2008; 2

Fentanyl…..contd

• Transdermal fentanyl : - Better pain control and quality of life in patients with - chronic pain in osteo or rheumatoid arthritis (Pavelka 2004)

• Effective alternative to oral morphine - in management of cancer pain ( Muijser 2004)

Pavelka K, Le Loet X, Bjorneboe O, Herrero-Beaumonf G, Richarz U. Benefits of transdermal fentanyl in patients with rheumatoid arthritis or with osteoarthritis of the knee or hip: an open label study to assess pain control. Curr Med Res Opin 2004; 20: 1967–77

Buprenorphine patches

Buprenorphine :

• Strong opioid derived from baine

• Two kinds of patch: - 4 day (Transtec patch ) - 7 day (Butrans patch) → both use a matrix design

Buprenorphine…contd

Buprenorphine patches :

- Useful in chronic cancer and non-cancer pain - A study in 13 179 patients - effective and sustained pain relief (Griessinger , 2005)

• 7 day buprenorphine patch: - Improved patient compliance - with treatment for 6 and 12 months ( when compared with codeine, dihydrocodeine, and tramadol )

- Side effects: nausea, vomiting, dizziness, and constipation

• Griessinger H, Sittl R, Likar R. Transdermal buprenorphine in clinical practice—a post-marketing surveillance study in 13179 patients. Curr Med Res Opin 2005; 21: 1147–56

Fentanyl HCl iontophoretic transdermal system(Fentanyl ITS)

A technique of introducing ionic medicinal compounds into the body through the skin by applying a local electric current

Fentanyl ITS:

• Only transdermal opioid - for management of acute pain

• Licensed for patient-controlled management (of moderate-to-severe postop. pain)

• Credit-card-sized patch - applied to upper outer arm or chest

• When ‘on-demand button’ is pressed twice within 3 s, a pre-programmed dose of 40 µg of fentanyl is delivered transdermally over a 10 min period

Fentanyl ITS

• Maximum - six doses delivered per hour - this cannot be changed

• A small LED indicates when a dose is being delivered

• Each system lasts for 24 hr or 80 doses - then discarded

• After discontinuation of fentanyl PCA, plasma conc. decrease at a rate similar to that following i.v. adm.

- suggesting →that there is no development of a skin depot

Fentanyl ITS system….contd

- Superior in moderate-to-severe pain after orthopaedic, abdominal, and thoracic surgery

- Provides equivalent analgesia to i.v. PCA morphine ( phase III trial )

- Adverse events : nausea, vomiting, and pruritis. (typical of opioid)

- erythema and itching ( in 13% pts)

- No reports of ventilatory depression

Local anaesthetic patches

• Used - to reduce the pain of venepuncture

• 5% lidocaine patch (Versatis) - used for symptomatic relief of neuropathic pain associated with post-herpetic neuralgia

- Has direct local action - well tolerated

- Limited systemic effects

- Side effect - application site reactions

- 40 times lower than toxic levels in adults

5% lidocaine patch….contd

• However, limited data supporting lidocaine 5% patch in post-herpetic neuralgia

• Small randomized controlled trials: (Power 2007) - confirmed that Versatis produced superior pain relief ( than placebo in short-term studies)

• A Cochrane review concluded : ‘there is insufficient evidence to recommend topical lidocaine as a first line

therapy in post herpetic neuralgia’

• Further studies are awaited

• Power I. Fentanyl HCliontophoretic transdermal system (ITS): clinical application of iontophoretic technology in the management of acute postoperative pain. Br J Anaesth 2007; 98: 4–11

Future of transdermal drug delivery

• Transdermal delivery of analgesics would become further popular as there are further improvements in design

• Research being performed to increase safety and efficacy

• To improve practical matters such as – - More precise drug delivery and - Increased duration of action

Future of TDDS…..contd

• Other potential improvements include : → improved transdermal technology to increase drug flux across skin by: - Altering the skin barrier or - Increasing the energy of the drug molecules

• After the successful design of patches using iontophoresis → various modes of ‘active’ transdermal technologies being investigated

Future of TDDS…..contd

New technologies include:

- Electroporation : short electrical pulses of high voltage to create transient aqueous pores in the skin

- Sonophoresis : uses low-frequency ultrasonic energy to disrupt stratum corneum

- Thermal energy: uses heat to make the skin more permeable and to increase the energy of drug molecules

- Magnetic energy, magnetophoresis,: investigated as a means to increase drug flux across the skin

Future of TDDS…..contd

• Many analgesic patches : - Formulation are at different trial stages

• Capsaicin 8% (Qutenza) : - 1 hr patch - Tested and approved by the FDA - Effective in post-herpetic neuralgia , HIV neuropathy

• Bupivacaine patch (Eladur) - Continuous delivery for 3 days (from a single application)

- Longer duration , faster onset, deeper tissue penetration

(than lidocaine patch) - Useful in localized neuropathic pain

• Sufentanil and oxycodone patches: - Are in trial phase - May be a useful addition to the formulary

General recommendations

• Patches should be applied to clean, dry, intact skin

• Old patches should be removed before new patches applied (to avoid overdose or toxicity)

• Used patches should be disposed by folding the patch in half, with the adhesive side adhering to itself prior to removal

General recommendations ……contd

• Heat exposure may increase drug absorption - lead to overdose and toxicity

• Some patches contain aluminium material - should be removed before MRI to avoid skin Burns

• Reservoir patches should never be cut - can lead to dose dumping and potential overdose

• Matrix-based patches should also not be cut - as dosing inaccuracies may occur

CONCLUSIONS

• TDDS offers pharmacological advantages over the oral route, as well as improved patient acceptability and compliance

• This has made TDDS an important area of pharmaceutical research

• Several analgesics in patch formulation are currently at different stages of development

• Studies into improved delivery systems may also make it possible for a wider range of analgesics to be delivered via a TDDS in the future

Thank You

Future of TDDS…..contd

• Transdermal patch : - underutilized tool for management of acute and chronic pain

• With improved delivery and a wider range of analgesics: - Popularity and applicability of this modality to deliver drugs to increase