Transcript transdermal approach to pain relief: present and future

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