Why Skin Matters in Chronic Pain

Why Skin Matters in Chronic Pain Charles E. Argoff, MD, CPE

Learning Objectives  Describe the basic neural innervation of the skin  Describe how knowledge of such can provide insight into disease mechanism  Describe how such knowledge may lead to improved treatment of chronic pain

Disclosure  Consultant/Independent Contractor: Boehringer Ingleheim, Gruenthal Pharmaceuticals, Depomed, Jazz Pharmaceuticals, plc, Insys Pharmaceuticals, Shinogi Pharmaceuticals  Grant/Research Support: Endo Pharmaceuticals, Forest Laboratories, Lilly USA LLC, Neurogesx, Pfizer Inc.

Disclosure (continued)  Honoraria: Boehringer Ingleheim,, Depomed Endo Pharmaceuticals, Forest Laboratories, Janssen, Jazz, King, Lilly USA LLC, Neurogesx, Nuvo Research, Pfizer Inc. Sanofi-Aventis, US, LLC  Speakers Bureau: Endo Pharmaceuticals, Forest Laboratories, Janssen Pharmaceuticals, Inc. Lilly USA LLC, Pfizer Inc., Neurogesx

Epidermal Innervation and Chronic Pain Epidermis is normally well innervated by C & Aδ fibers

Simone et al. J Neurosci 1998;18:8947-8959

Epidermal Keratinocytes and Chronic Pain

Keratinocytes normally have a wide variety of neurosignaling molecules Signaling System

References

Acetylcholine

(Grando, Kist et al. 1993; Grando, Horton et al. 1995; Grando, Zelickson et al. 1995; Grando, Horton et al. 1996; Grando 1997; Ndoye, Buchli et al. 1998; Haberberger and Bodenbenner 2000; Sharma and Vijayaraghavan 2002; Elwary, Hasse et al. 2004; Kurzen and Schallreuter 2004; Nguyen, Chernyavsky et al. 2004; Metzger, Just et al. 2005; Eglen 2006; Elwary, Chavan et al. 2006; Hasse, Chernyavsky et al. 2007; Kurzen, Wessler et al. 2007; Moriwaki, Yoshikawa et al. 2007)

Cannabinoid

(Maccarrone, Di Rienzo et al. 2003; Stander, Schmelz et al. 2005; Ibrahim et al. 2005)

Catecholamine (Dopamine, Epinephrine, Norepinephrine)

(Flaxman and Harper 1975; Harper and Flaxman 1975; Gazith, Cavey et al. 1983; Orenberg, Pfendt et al. 1983; Cavey, Cavey et al. 1986; Koizumi, Yasui et al. 1991; Schallreuter, Wood et al. 1992; Ramchand, Clark et al. 1995; Schallreuter, Lemke et al. 1995; Schallreuter, Korner et al. 1996; Koizumi, Tanaka et al. 1997; Schallreuter 1997; Botchkarev, Peters et al. 1999; Gillbro, Marles et al. 2004; Fuziwara, Suzuki et al. 2005; Pullar, Rizzo et al. 2006)

Endothelin

(Imokawa, Yada et al. 1992; Yohn, Morelli et al. 1993; Yohn, Smith et al. 1994; Bagnato, Venuti et al. 1995; Tsuboi, Sato et al. 1995; Pernet, Mayoux et al. 2000; Hirobe 2001; Jamal and Schneider 2002; Fujioka, Nakamura et al. 2003; Khordorova et al. 2003; Okazaki, Yoshimura et al. 2005; Oshita, Lee et al. 2006)

GABA

(Canellakis, Milstone et al. 1983; Stoebner, Carayon et al. 1999; Denda, Inoue et al. 2002; Denda, Fuziwara et al. 2003; Warskulat, Reinen et al. 2004)

Glutamate

(Morhenn, Waleh et al. 1994; Genever, Maxfield et al. 1999; Fischer, Glanz et al. 2004; Nahm, Philpot et al. 2004; Fischer, Fiedler et al. 2006)

Histamine

(Fitzsimons, Duran et al. 1999; Fitzsimons, Engel et al. 2001; Fitzsimons, Engel et al. 2002; Giustizieri, Albanesi et al.

2004; Matsubara, Tamura et al. 2005; Cannon, Chazot et al. 2007)

Keratinocytes normally have a wide variety of neurosignaling molecules Signaling System

References

Neuropeptide (CGRP, SubP)

(Koizumi, Tanaka et al. 1992; Koizumi, Yasui et al. 1994; Bae, Matsunaga et al. 1999; Kiss, Kemeny et al. 1999; Staniek, Doutremepuich et al. 1999; Song, Bunnett et al. 2000; Albertin, Carraro et al. 2003; Dallos, Kiss et al. 2006; E, Golden et al.

2006; Liu, Hu et al. 2006; Yu, Li et al. 2006)

Opioid

(Shah and Borchardt 1990; Schauer, Trautinger et al. 1994; Nissen and Kragballe 1997; Bigliardi, Bigliardi-Qi et al. 1998; Bigliardi-Qi, Bigliardi et al. 1999; Egeling, Muller et al. 1999; Bigliardi, Buchner et al. 2002; Bigliardi-Qi, Sumanovski et al.

2004; Salemi, Aeschlimann et al. 2005)

Purinergic (ATP, ADP, UTP)

(Pillai and Bikle 1992; Cook, Ashton et al. 1995; Dixon, Bowler et al. 1999; Lee, Choi et al. 2001; Denda, Inoue et al. 2002; Burgstahler, Koegel et al. 2003; Burrell, Bowler et al. 2003; Doebler 2003; Greig, James et al. 2003; Mizumoto, Mummert et al.

2003; Koizumi, Fujishita et al. 2004; Burrell, Wlodarski et al. 2005; Inoue, Denda et al. 2005; Metcalfe, Baker et al. 2006; Yoshida, Kobayashi et al. 2006; Pastore, Mascia et al. 2007)

Serotonin

(Slominski, Pisarchik et al. 2002; Slominski, Pisarchik et al. 2003; Slominski, Pisarchik et al. 2003; Huang, Li et al. 2004; Slominski, Wortsman et al. 2005)

Vanilloid (TrpV)

(Southall, Li et al. 2003; Chung, Lee et al. 2004; Lee and Caterina 2005; Denda, Sokabe et al. 2007)

Target Cellkeratinocytes Interactions:express Epidermal Keratinocytes Epidermal analgesic mechanisms • CB2 and ETB receptor activation leads to keratinocyte-derived β-endorphin.

• µ-opioid receptors on a subset of epidermal endings – tonic analgesic mechanisms.

Khodorova et al., Nature Med. (2003); Ibrahim et al., PNAS (2005)

Target Cell Interactions: Epidermal Keratinocytes Painful glabrous hindpaw following L5/L6 SNL • Following SNL in rat, there is a loss of analgesic mechanisms β-endorphin, ETB, and

CB2 in the epidermis.

Control

SNL

β-endorphin

ETB

CB2 Albrecht & Rice, 2008 unpublished

Epidermal Target CellKeratinocytes Interactions: Epidermal express algesic Keratinocytes mechanisms

•Keratinocytes express voltage-gated sodium channels (Nav) in skin.

• Nav mediates a release of ATP from cultured keratinocytes.

• ATP can activate purinergic receptors on a subset of epidermal endings.

•Keratinocyte release of ATP is implicated as part of a differentially stratified neural signaling mechanism of sensory transduction, integration, and regulation.

Target Cell Interactions: Epidermal Keratinocytes Epidermal Keratinocytes express algesic mechanisms • Nav ion channels play a direct role in neuron action potential generation • Epidermal Nav expression is increased among keratinocytes from painful human skin.

• Nav activation in KC are not fully defined.

• Likely involved in ATP release and activation of purinergic receptors.

Neurosignaling molecules are normally stratified in such a way that implicates the keratinocytes in sensory transduction and integration.

Target Cell Interactions: Epidermal Keratinocytes Epidermal Keratinocytes express CGRP in Chronic Pain • Keratinocyte CGRP expression is increased among keratinocytes from painful CRPS human skin

Target Cell Interactions: Epidermal Keratinocytes Epidermal Keratinocytes express CGRP after nerve injury • Increased expression of CGRP is evident in epidermal keratinocytes following rat models of experimentally- induced mechanical allodynia and thermal hyperalgesia.

Target Cell Interactions: Epidermal Keratinocytes Keratinocytes express the beta isoform of CGRP • Calcitonin gene-related peptide (CGRP) mRNA expression in transgenic mouse epidermal keratinocytes in vivo, and normal human keratinocytes in vitro

Target Cell Interactions: Epidermal Keratinocytes CGRP and Nav channels in Human chronic pain after treatment with a known therapeutic

Target Cell Interactions: Epidermal Keratinocytes CGRP interactions with Nav channel fluctuations in Human chronic pain after treatment with a known therapeutic

Vascular Innervation and Chronic Pain

ACKNOWLEDGEMENTS Albany Medical College: Phillip Albrecht Travis Barr Quanzhi Hou Michel ParĂŠ Chris Noto Paul McMahon Keri Cannon Lindsay Hough Marilyn Dockum James Wymer Charles Argoff

Genetic Studies: David Anderson Mark Zylka Udayan Guha John Kessler Rodent Pain Models: Ke Ren Ron Dubner Robert LaMotte Mary Barbe

Epidermal Mechanisms: Frank Porreca Mohab Ibrahim Tamara King Gudarz Davar Alla Khodorova Gary Strichartz Peng Zhao Joel Black Steve Waxman Sulayman D. Dib-Hajj

Congenital analgesia with hyperhydrosis: Diabetic Neuropathy & Vasculopathy: David Bowsher Barbara Hansen Pharmaceutical support: Geoffrey Wood Gary Pittenger Astra Zeneca Aaron Vinik CRPS I: Johnson & Johnson Elon Eisenberg Postherpetic Neuralgia: Amgen Merck Dorit Pud Michael Rowbotham Endo Lilly Kari Connolly Karin Petersen Vertex Forest

Current Clinical Applications  Neuropathic Pain  Soft Tissue Injuries  Osteoarthritis  Chronic Low Back Pain  Other

Topical Analgesics: Key Facts  Topical agents are active within the skin, soft tissues and peripheral nerves.  In contrast to transdermal, oral or parenteral medications, use of a topical agent does not result in clinically significant serum drug levels.  Other benefits include lack of systemic side effects and drug-drug interactions.  The mechanism of action of a topical analgesic is unique to the specific agent considered.

Topical Treatments for Chronic Pain  Local anesthetics – Lidocaine patch 5%/eutectic mixture of local anesthetics – Diclofenac (patch/gel/lotion)

 Capsaicin  Aspirin  Tricyclic antidepressants  Opiates  Investigational agents/Compounded

Neuropathic Pain  Clinical trial data provides varying levels of evidence for the use of certain topical analgesics in the treatment of neuropathic pain  The lidocaine 5% patch is FDA approved for the treatment of PHN

Neuropathic Pain (continued)  Clinical trials of PHN patients which led to the FDA approval demonstrated that use of the lidocaine 5% patch by patients compared to use of placebo patches resulted in statistically significant more pain reduction and was in addition safe and well-tolerated

Clinical Trials

Neuropathic Pain

Neuropathic Pain  Several other non-controlled studies of patients with painful diabetic neuropathy who were treated with the lidocaine 5% patch have been completed. These studies allowed patients to use as many as four lidocaine 5% patches for as long as 18 hours/day .

Neuropathic Pain  Also of great interest are the results of a functional brain MRI study of patients with PHN who were treated with the 5% lidocaine patch for various time periods. Depending upon the length of application, brain activity for the spontaneous pain of PHN, appeared to be modulated by treatment with this medication, again suggesting that a peripherally acting agent may have an impact on central pain mechanisms .

Neuropathic Pain  In a randomized, controlled study of PHN patients, treatment with the eutectic preparation of 2.5% lidocaine and 2.5% prilocaine cream did not result in significant differences between the treated and placebo groups. In a two studies, each of which were uncontrolled and thus less rigorously designed, the results were more encouraging suggesting that use of the eutectic preparation of 2.5% lidocaine and 2.5% prilocaine cream might relieve the pain associated with PHN.

Neuropathic Pain  There has been great interest in using capsaicin in a number of neuropathic pain disorders such as diabetic neuropathy, painful HIV neuropathy, PHN and post-mastectomy pain, but past available strengths of capsaicin (.025% and .075%) had yielded disappointing results with the treatment being poorly tolerated, regimens poorly adhered to and not enough pain relief experienced.

Neuropathic Pain  Recently, the 8% capsaicin patch (Qutenza) has received FDA approval for the treatment of PHN. In studies leading to its FDA approval it was shown to be more effective in reducing pain intensity than an active, lower concentration capsaicin product that served as placebo and it was generally well tolerated. It has also been studied in other neuropathic pain states such as painful HIV neuropathy with favorable outcome as well.

Neuropathic Pain  There has been interest in the use of topical tricyclic antidepressants in the treatment of neuropathic pain with clinical trials completed. In each two such studies, the preparation tested was a combination of amitriptyline 2% /ketamine 1%.

Neuropathic Pain (continued)  The results of one of these, a double blind randomized placebo controlled study involving 92 patients with diabetic neuropathy, PHN, post surgical, or posttraumatic neuropathic pain, there was no difference in pain relief among the four treatment groups (placebo, amitriptyline 2% alone, ketamine 1% alone or the combination amitriptyline2%/ketamine 1%).

Neuropathic Pain  A 35-year-old female with complex regional pain syndrome type 2 following a traumatic injury to her left peroneal nerve presents to your office for evaluation and treatment. She is married with two children and is currently working part-time as an accountant. She is utilizing several medications and complains of severe, burning pain and hypersensitivity to anything that touches her left leg and foot, with a visual analogue scale score of 6/10.

Neuropathic Pain  The pain is continuous but worst at night. She has achieved 30% pain relief taking both duloxetine and pregabalin at maximally tolerated doses. She has failed a trial of both spinal as well as peripheral nerve stimulation and had previously benefitted only temporarily from sympathetic nerve blocks.

Should this person be treated as well with a topical analgesic, even in an “off-label� manner? If so, which and what evidence do we use in making this decision?

Neuropathic Pain  The pain is continuous but worst at night. She has achieved 30% pain relief taking both duloxetine and pregabalin at maximally tolerated doses. She has failed a trial of both spinal as well as peripheral nerve stimulation and had previously benefitted only temporarily from sympathetic nerve blocks.

Should this person be treated as well with a topical analgesic, even in an “off-label� manner? If so, which and what evidence do we use in making this decision?

Soft Tissue Injuries/Osteoarthritis  Soft tissue injuries and osteoarthritis are each an example of musculoskeletal pain states. The use of topical analgesics for these heterogeneous conditions has been actively studied and in fact since 2007 the FDA has approved three topical NSAIDs.

Soft Tissue/OA (continued)  The diclofenac sodium gel 1% ( Voltaren gel 1%) was FDA approved for use in treating pain associated with OA in joints that can be managed with topical treatment such as the knees and hands. The diclofenac epolamine topical patch (Flector patch) has been FDA approved for the topical treatment of acute pain due to minor strains, sprains and contusions. The diclofenac sodium topical solution (Pennsaid) has been FDA approved for the treatment of the signs and symptoms of OA of the knee .

Soft Tissue/OA (continued)  Outside of the US, other topical NSAIDs have been studied.

The use of a topical ketoprofen patch (100mg) was superior to placebo in reducing pain after one week of treatment in a 14 day randomized, placebo controlled study of 163 patients with an ankle sprain (France). A similar ketoprofen preparation has been studied in patients with tendonitis in a randomized, double-blind, placebo controlled study. Results were positive in favor of the active treatment and the treatment was in general, except for skin irritation, well tolerated.

Soft Tissue/OA (continued)  In a child with Sever disease, a common cause of heel pain in athletic children, ketoprofen gel has been used as adjunctive therapy to physical therapy with reported benefit.

Soft Tissue/OA (continued)  One should recognize that topical salicylates are used by patients in non-prescription preparations. A meta-analysis examining the effects of topical salicylates in acute and chronic pain concluded that based on the sparse data available that use of topically applied rubefacients containing salicylates based upon available trials of musculoskeletal and arthritic pain resulted in moderate to poor efficacy

Soft Tissue/OA (continued)  No benefit of 0.025% capsaicin crèam over vehicle (not active) cream in a randomized, double-blind study of 30 patients with pain in the temporomandibular joint has been noted.  A topical cream containing glucosamine sulfate, chondroitin sulfate and camphor for osteoarthritis of the knee showed a significant reduction of pain in the treatment group after 8 weeks compared to the placebo group in a randomized controlled study.

Soft Tissue/OA (continued)  A recently published case series reported the potential benefit of “topical” morphine in the management of chronic osteoarthritis related pain; however, since the report emphasized that morphine or its metabolites were identifiable in the urine of treated patients it is unclear how truly “topical” this preparation was.

Soft Tissue/OA (continued)  Case Report: Consider a 67 year old female with osteoarthritis of both knees, and severe hypertension and esophageal reflux, who may be considered to be an inappropriate candiadate for an oral NSAID, who has had little to no response to opiates, injection therapy and /or physical therapy and is not a candidate for knee replacement. Might she be a candidate for a topical analgesic?

Chronic Low Back Pain/Myofascial Pain ď&#x201A;§ Far fewer studies regarding the use of topical analgesics for low back pain or myofascial pain have been published ď&#x201A;§ The results of a double-blind, placebo controlled study comparing topical capsaicin to placebo in 154 patients with chronic low back pain indicated that 60.8% of capsaicin treated patients compared with 42.1% of placebo patients experienced 30% pain relief after 3 weeks of treatment (p<0.02)

CLBP/MP (continued) ď&#x201A;§ A multicenter, open-label study involving treatment of 120 patients with acute (< 6 weeks), subacute (<3 months), short-term chronic (3-12 months) or long-term chronic (> 12 months) low back pain with the 5% lidocaine patch was completed. During the 6-week study period, participants applied four lidocaine 5% patches to areas of maximal low back pain every 24 hours. Initial evaluation suggests that the majority of patients experience moderate or greater degree of pain relief.

Summary ď&#x201A;§ Skin DOES matter with respect to disease pathophysiology, disease diagnosis and treatment ď&#x201A;§ Since use topical analgesic use is generally associated with a better side effect profile than orally, transdermally, parenterally or intrathecally administered analgesics, this should be considered when developing a pharmacologic treatment regimen for an individual patient

References  Argoff CE. New analgesics for neuropathic pain: the lidocaine patch. Clin J Pain 2000;Suppl 16(2):S62-65.  Argoff CE. Targeted Topical Peripheral Analgesics in the Management of Pain. Curr Pain Headache Rep.. 2002 Feb;7(1):34-38.  Galer BS. Topical medications. In: Loeser JD, ed. Bonica’s Management of Pain. Philadelphia: Lippincott-Williams & Wilkins; 2001:1736-1741.

References (continued)  Argoff C, Nicholson B, Moskowitz M, et al. Effectiveness of lidocaine patch 5% (Lidoderm®) in the treatment of low back pain. Presented at the 10th World Congress on Pain, August 1722, 2002, San Diego, CA.  Watson CPN. Topical capsaicin as an adjuvant analgesic. J Pain Symptom Manage. 1994;9:425-433.  Gammaitoni AR, Davis MW. Pharmacokinetics and tolerability of lidocaine 5% patch with extended dosing. Ann Pharmacother. 2002;36:236-240.

References (continued)  Ness TJ, Jones L, Smith H. Use of compounded topical analgesics- results of an Internet survey. Reg Anesth Pain Med. 2002 May-Jun:27(3):309-312.  Sawynok J. Topical and peripherally acting analgesics.

Pharmacol Rev 2003 55:1-20.  Robbins W. Clinical applications of capsaicinoids. Clin J Pain 2000;Suppl 16(2):S86-89.

References (continued) ď&#x201A;§ Sawynok J, Esser MJ, Reid AR. Antidepressants as analgesics: an overview of central and peripheral mechanisms of action. J Psychiatry Neurosci 2001;26(1):21-29. ď&#x201A;§ Gerner P, Kao G, Srinivasa V, et al. Topical amitriptyline in health volunteers. Reg Anesth Pain Med. 2003 JulAug;28(4):289-93.

References (continued)  Meier T, Wasner G, Faust M, et al. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 2003;106:151-158  Argoff CE. Topical treatments for pain. Current Pain and Headache Reports. 2004; 8:261-267.  Bley KR. Recent developments in transient receptor potential vanilloid receptor 1 agonist based therapy. Expert Opin Investig Drugs. 2004 Nov;13(11):1445-56.

References (continued)  Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004 Apr24;328(7446):991-996.  Sawynok J. Topical analgesics in neuropathic pain. Curr Pharm Des. 2005;11(23):2995-3004.  Lynch ME, Clark AJ, Sawynok J, et al. Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial.

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