Pain Management: Neuropathic Pain

Topical therapies and combination preparations could have several advantages over systemically administered analgesics, including the ability to supply powerful analgesia with reduced systemic drug levels, an element especially beneficial to the elderly. Fewer negative effects combined with advantageous and painless management results in improved individual popularity and conformity, and ease of use will lessen total treatment bills. Because they are applied straight to the target site, topical management will offer healing levels inside the cells beneath the region of application, with minimal serum degrees. Lower systemic drug levels possibly lower the danger of organ toxicity. Additionally, initially worrisome hepatic metabolism and alternative factors associated with the gastrointestinal system are prevented. Topical therapy is a worthwhile answer which avoids the requirement for injections whenever oral dosing is not feasible, considering the individual is nauseated or unconscious.

Existing commercially-available treatments may have limited effectiveness and produce relatively frequent adverse effects. Patients often convey that different medications will impart distinct analgesic benefits. Presence of side effects such as insomnia, depression, anxiety, and fatigue can diminish the patient’s quality of life, and justify a change to a customized therapy.

There is a growing body of evidence on the efficacy and safety of topical agents in a variety of pain disorders, including the most prevalent neuropathic pain conditions. The molecular basis for the usage of peripheral analgesics in neuropathic pain and the available clinical trial evidence for a wide variety of topical agents are reviewed in an excellent article by Oscar A. de Leon-Casasola, MD, Department of Anesthesiology and Critical Care Medicine, Roswell Park Cancer Institute, School of Medicine and Biomedical Studies, State University of New York at Buffalo. Agents “that profoundly reduce neurotransmitter release from nociceptors generating ectopic pulses, such as topical local anesthetics and anticonvulsants, may relieve neuropathic pain. Likewise, increased peripheral sensitivity mediated through the release of prostaglandin E2 and substance P at the peripheral level results in spontaneous discharges that may be inhibited by topical drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs)… Additionally, topical substance P inhibitors and ketamine can reduce the effects of substance P, while sympathetic afferent activation can be modified by the topical administration of a beta-blocker and clonidine. Topical antihistamine may decrease the release of histamine and serotonin, thereby limiting the inflammatory process and hindering vasodilation. Topical opioids can target the opioid receptors present on nociceptive fibers and mast cells. Binding of opioid receptors can inhibit the release of the calcitonin gene-related peptide (CGRP) and substance P from nerves, thereby preventing the feed-forward mechanism of pain that typically results in sensitization at the site of injury (primary hyperalgesia).” Pentoxifylline has effectively provided relief for some neuropathic conditions when applied topically. “Topical tricyclic antidepressants, such as doxepin and amitriptyline, have demonstrated efficacy in a number of neuropathic pain states.”

Neuropathic pain is usually immune to opioids, thus additional drugs classes – including tricyclic antidepressants, anticonvulsants, and nearby anesthetics are usually utilized. Central sensitization, or pain “wind-up,” might perpetuate chronic neuropathic pain even if continuous peripheral sensory input is missing. Wind-up is thought to result allodynia, hyperalgesia, and hyperpathia. Receptors including NMDA, AMPA, and M-glu have newly been diagnosed for their role in central sensitization, and antagonists of these receptors have yielded pain relief.

The analgesic impact of tricyclic antidepressants is independent of their antidepressant activity andusually happens at low dosages with onset of pain relief inside 1 to 2 weeks. For instance, the analgesic impact of topically used doxepin hydrochloride in chronic human neuropathic pain was described in a randomized, double-blind, placebo-controlled research of 220 adult people. Fewer negative effects were reported compared with oral management.

Med Clin North Am. 2007 Jan;91(1):113-24.

Adjuvant analgesics.

Knotkova H, Pappagallo M.

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J Pain Symptom Manage. 2007 Mar; 33(3):356-64.

Transdermal Lidocaine and Ketamine for Neuropathic Pain: A Study of Effectiveness and Tolerability

Emily Tam plus Andrea D Furlan

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Reg Anesth Pain Med 2003 Jul-Aug;28(4):289-93

Topical amitriptyline in healthy volunteers.

Gerner P, Kao G, Srinivasa V, Narang S, Wang GK.

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Pain Clin 2000;12(1):47-50.

No abstract accessible.

Dextromethorphan/Quinidine for Treatment of Diabetic Neuropathic Pain

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. The most frequent form, estimated to affect 50% of diabetic patients, is a distal symmetric polyneuropathy. The associated pain, which affects approximately 25% of DPN patients, can be severe and disabling.

In a 13-week, phase 3, randomized double-blind controlled trial, 379 adults with daily symmetric diabetic peripheral neuropathy (DPN) leg pain of 3 months duration received placebo, dextromethorphan/quinidine (DMQ) 45/30 mg, or DMQ 30/30 mg, administered once daily for 7 days and twice daily thereafter. The results of this study demonstrate that DMQ was more effective than placebo in the treatment of DPN pain at both dose levels studied.

Pain Med. 2012 Feb;13(2):243-54.

Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study.

Shaibani AI, Pope LE, Thisted R, Hepner A.

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Topical Glycopyrrolate to Relieve Neuropathic Pain in Lower Extremities

A patient reported that lower extremity sweating was a reliable predictor of soon-to-increase painful “sparking” and burning pain. A trial of topical 2% glycopyrrolate cream (compounded by a community pharmacist) was instituted, based on reports of its use in Frey syndrome. During an episode where both feet were painful and sweating, 2% glycopyrrolate was applied to the most painful foot, and capsaicin 0.25% to the other. The patient found that treatment with 2% glycopyrrolate better alleviated the neuropathic symptoms compared with capsaicin. This case suggests that hyperhidrosis may be an index symptom for an underlying pathobiological driver of neuropathic pain in patients with painful sweating.

Pain Med. 2012 Mar;13(3):484-5.

The beneficial effect of topical glycopyrrolate in a patient with neuropathic lower extremity pain.

Schwartz L, Quezado Z.

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This study evaluated the effects of a topical gel containing baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) on numbness, tingling, and pain caused by chemotherapy-induced peripheral neuropathy. The study concluded that BAK-PLO was well tolerated without evidence of systemic toxicity and appeared to somewhat improve symptoms of CIPN.

Support Care Cancer. 2010 May 25. [Epub ahead of print]

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.

Barton DL et al.

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Study subjects with moderate to severe peripheral neuropathic pain found that use of topical 2% amitriptyline/1% ketamine cream was well tolerated and was associated with long-term reduction in perceived pain.

J Pain. 2005 Oct;6(10):644-9.

Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study.

Lynch ME, Clark AJ, Sawynok J, Sullivan MJ.

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Topical Clonidine for Diabetic Neuropathy

A phase 2b double-blind, randomized, placebo-controlled clinical trial, showed that a topical clonidine 0.1% gel relieved pain in adults with painful diabetic neuropathy, and no serious side effects were reported.

Amitriptyline/Ketamine Topical Cream for Treating Post-Herpetic Neuralgia (PHN)

Combinations of synergistic drugs are customized for the individual with chronic pain, andtopical or transdermal formulations provide good alternatives, occasionally with fewer negative effects compared to the same drugs whenever taken orally.  A multicenter, double-blind, randomized, placebo controlled research was performed to evaluate the efficacy and protection of amitriptyline 4%/ketamine 2% [NP-H] and amitriptyline 2%/ketamine 1% [NP-L] topical lotions versus placebo in 251 PHN people. NP-H was numerically superior to NP-L cream and placebo and appears to become the optimum focus for PHN treatment. Less than 5% of topics who used NP-H had detectable serum degrees of amitriptyline or ketamine.

This research was presented at the 2007 American Pain Society Annual Meeting, Poster #787

The following article discusses the use of topical ketamine 0.5% (5 mg/ml) gel, applied as a thin film two to three times daily over the skin where pain was severe. Topical ketamine reduced pain for people with postherpetic neuralgia without systemic negative effects.

Neurology 2003;60:1391-1392

Topical ketamine treatment of postherpetic neuralgia

No abstract accessible. Click here to buy the full post online.

The following randomized, double-blind, placebo-controlled study assessed the analgesic efficacy of topical administration of 3.3% doxepin hydrochloride, 0.025% capsaicin, or a combination applied daily for 4 weeks in 200 adult patients with chronic neuropathic pain, and reported that all three preparations significantly reduced overall pain.

Br J Clin Pharmacol 2000 Jun;49(6):574-9

Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study.

Click here to access the PubMed abstract of the post.