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TRANSDERMAL APPROACH TO PAIN RELIEF: PRESENT AND FUTURE S K MALHOTRA Department 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: - Co: - P: - h: diffusion coefficient constant concentration of drug in the patch partition coefficient between skin and bathing solution 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 • Short half-life (effective at low dosage) 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 • Tetracaine • Lidocaine 5% (Ametop) (Versatis) (Rapydan) 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