Saturday, January 1, 2011

Is There a Role for Topical Opioids in Pain Care?

Topical OpioidsTopical medications have been used for ages and are delivered via a variety of dosage formulations including creams, ointments, gels, lotions, solutions, pastes, and sprays. Agents applied topically specifically for analgesia have traditionally included various NSAIDs, capsaicin, local anesthetics (eg, lidocaine), rubefacients or counterirritants (eg, menthol, camphor, others), and herbal products (eg, arnica, comfrey, and others). For unknown reasons, the topical application of opioids has been largely overlooked; yet, such formulations might be a safe and effective alternative for the better care of many acute and chronic pain conditions.

For example, there are only 9 clinical trials currently registered involving topical opioids and all are studying effects on painful acute wounds [see,]. A recent and otherwise good review of topical analgesics incorrectly lists fentanyl and buprenorphine transdermal patches as topical opioids; however, while these agents are applied topically they are intended to enter the bloodstream and have systemic rather than localized or peripheral effects [Moody 2010]. The Cochrane Collaboration has only recently planned a first-ever systematic review of the literature on topical analgesics that also will include topical, peripherally-acting opioids [Moore et al. 2010].

Revising Traditional Perspectives
The traditional perspective is that opioid pain-relieving effects take place systemically within the central nervous system. Beginning with animal experiments, the existence of peripheral opioid receptors that could be affected by topically applied opioid agents were explored well over 20 years ago. In limited human trials, largely published as case-study reports, topical opioids appeared to offer therapeutic options with numerous advantages over oral opioids for acute or chronic cancer or noncancer pain conditions. It should be noted, however, that topical formulations of opioids are an “off-label” application in the U.S., as there currently are no FDA-approved, commercially available preparations. However, compounding pharmacies can, and do, readily formulate topical mixtures containing prescribed opioids, often in combination with additional prescribed ingredients. [See disclaimer below.]

Further research discovered that, anatomically, many types of pain sites are essentially wounds containing inflammatory compounds spurring a proliferation of opioid receptors along with increases in sensory nerve terminals. All 3 opioid receptor types (mu, delta, kappa) can be present and active in peripheral tissues, and the function of these inflammatory processes is to attract the body's natural endorphins for pain relief. These endogenous opioid peptides are expressed by resident immune cells in inflamed peripheral tissues, resulting in analgesic effects. The peripheral opioid receptors can modulate nerve impulses in a way similar to the action of opioid receptors in or near the spinal cord, so exogenous opioids such as morphine applied at pain sites have effects akin to systemic opioids (administered orally or parentally) that impact the central nervous system [Stein 1995; Watterson et al. 2004].

A major and critical difference is that peripherally acting opioids allow analgesia without undesirable central side effects, such as respiratory depression, dysphoria, sedation, nausea, or addiction, and without the adverse effects of systemic or topical NSAIDs (eg, renal toxicity, gastric bleeding, cardiovascular effects). The fact that peripheral opioid actions are particularly prominent in inflamed tissues may be clinically advantageous, considering that many acute or chronic pain conditions are associated with inflammation (eg, trauma, postoperative pain, pain due to cancer or arthritis, and myofascial pain). Furthermore, the involvement of immune cells in pain inhibition may provide new insights into pain associated with a compromised immune system, as in cases of AIDS, other autoimmune disorders, and certain cancers [Stein 1995; Watterson et al. 2004].

Topical Opioid Successes
Not all opioids are suitable for topical pain relief, according to Forest Tennant, MD, who has extensively used this modality in patients with chronic pain [2010A]. The opioids he most commonly prescribes topically are morphine, hydromorphone, and oxycodone, which penetrate gradually through skin and act directly on opioid receptors without requiring further metabolism. He notes that some patients use methadone topically and find it effective. Certain opioids — such as hydrocodone, codeine, and tramadol — are prodrugs, requiring hepatic conversion to active analgesic metabolites, and remain inert on the skin surface. Fentanyl is extremely soluble and dissolves quickly through the skin making it an effective systemic agent but a poor choice for topical use, and there has been no mention in the literature thus far regarding the use of oxymorphone in topical formulations.

Following, are some examples from the literature reporting effective applications of topical opioids. Specific formulations also are noted, to the extent that they were indicated in the reports.
  • In a conference poster presentation, Tennant reported a case series of 33 patients with long-term intractable pain who self-administered prescribed topical opioids [2010B]. Patients ranged from 29 to 82 years of age, with pain due to spine degeneration (61%), neuropathies (24%), or arthritis (15%). They used one of 3 formulations — morphine (30 mg or 90 mg), oxycodone (30 mg or 90 mg), or hydromorphone (8 mg or 24 mg) per ounce of base cream — and they were issued up to 16 ounces/month during 6 months for PRN (“as needed”) application. All patients reported using their cream at least once daily, with many (67%) also using it for breakthrough pain or flares.

    The vast majority of patients (85%) reported effective pain relief lasting up to 3 hours from single topical opioid applications. A significant number (62%) used inexpensive heat, vibrator, infrared, or ultrasound devices over the application area to enhance absorption. Added benefits reported by 30% or more of patients included: decreased use of oral opioids, fewer or less severe pain flares, and less stiffness. Smaller numbers of patients also noted being more active, enjoying more sleep, appetite improvement, and/or better self-control over pain.

  • In an earlier report, Tennant [2010A] described case reports of patients who used mixtures containing 1 to 2 of the following opioid tablets per ounce of common cold cream: morphine 30 mg, hydromorphone 4 mg or 8 mg, or oxycodone 30 mg. Patients were instructed in crushing the tablets and formulating the mixture themselves, and many found other creams, oils, lotions, or gels that seemed to work better for them. [Note: This home-compounding might have the disadvantage of producing coarse mixtures without an even distribution of active ingredient.]

  • In a much earlier report, appearing in The Lancet, Tennant et al. [1993] reported on 26 patients with severely painful back conditions who used a mixture containing 120 mg morphine in 80 grams of a moisturizing cream (Aquaphor). From 1 mg to 3 mg was applied daily and treated with ultrasound to enhance penetration. Most patients (88%) noted up to 40% or 50% localized pain relief for 4 or more hours, and 19% reported relief lasting longer than a day.

    Using the same approach, Tennant’s team also conducted a small, placebo-controlled, double-blind, crossover study. As expected, average duration of pain relief was significantly greater with the topical opioid than placebo cream. Pain-free, body-movement 24 hours after treatment was reported in 44% of the morphine cream applications compared with none of the placebo applications.

  • In a recent Letter to the Editor, Marshall J. Ney, DMD, a practitioner in a headache clinic, reported using a topical mixture of morphine (60 mg immediate release), dimethyl sulfoxide (DMSO), and aloe vera gel (as a diluent) [Ney 2010]. He noted remarkable improvement in his patients in terms of pain relief and, thereby, psychological well-being — without systemic opioid adverse effects.

    DMSO is a very interesting agent, discovered in 1866 as a byproduct of paper manufacturing. Used as an industrial solvent, it also has a high capacity to penetrate skin and tissues. Going back at least 5 decades, sometimes controversial claims have been made regarding health benefits of DMSO, including potent analgesic effects; however, it is only FDA-approved to treat interstitial cystitis, a painful bladder condition, and some states prohibit its use for other medical applications. Animal experiments had demonstrated properties of DMSO as an effective carrier agent facilitating transport of topically applied opioids through the skin [Kolesnikov et al. 2000]. Indeed, a newer topical NSAID product, containing diclofenac sodium (Pennsaid®), incorporates a 45.5% solution of DMSO, presumably as an inactive carrier agent; so, this may portend future uses of DMSO in topical analgesic products. [For further information on DMSO, click here.]

  • Jacobsen [2010] described randomized, double-blind, placebo-controlled studies (but encompassing only a total of 34 subjects) to assess the efficacy of a topical opioid mixture (10 mg morphine/8 gm amorphous hydrogel) for treating painful ulcers (mostly sacral pressure ulcers). Compared with placebo, the topical opioid produced significantly improved pain scores, with decreases of 2 to 3 points on a 0-10 pain scale. In other research enrolling patients with painful oral mucositis, rinses with 0.2% morphine solution (2000 mg morphine chlorohydrate in 1000 mL of water) produced a significantly decreased duration and intensity of pain as compared with a mixture of lidocaine, diphenhydramine, and magnesium aluminum hydroxide. The morphine-rinse protocol consisted of 15 mL taken every 3 hours PRN and held in the mouth for 2 minutes before expectoration.

  • Waterson and colleagues [2004] reported the first clinical use of topical opioids for severely inflamed skin lesions in young children. The treatment produced good pain relief without side effects, and they also found improved healing as an incidental but important benefit. The very low dose of topical morphine used — 0.2 mg/kg, or a 0.06% mixture in hydrogel — was considered safe even if rapidly absorbed. They proposed that the technique could also help management of other painful skin lesions, including burns, ulcerated vascular hemangiomas, or postoperative wounds.

  • In an interesting experiment using an animal model, Tandon and colleagues [2010] recently reported that low-dose naloxone (LDN) administered topically in combination with morphine and ketamine (an NMDA antagonist) produced significant and synergistic analgesic effects. [We have previously discussed analgesic benefits of centrally-acting low-dose naloxone and naltrexone (here), and this observed peripheral action could be of significance for developing topical opioid formulations.]

  • Other recent research in animals found that the combination of topically administered mu- and delta-opioid receptor agonists had a synergistic analgesic effect [Schramm and Honda 2010], and topical combinations of low-dose lidocaine with either low-dose morphine, levorphanol, or buprenorphine yielded significant additive effects producing greater analgesia than each agent alone [Kolesnikov et al. 2000]. Of interest, topical buprenorphine was 5-fold more potent than topical morphine in this animal model, and the lidocaine-buprenorphine combination had the greatest potency and longest duration of action.
An impressive feature of the research to date is the diversity of topical opioids, plus combinations with other agents in many cases, that may produce effective analgesia in a variety of pain conditions. However, much of the evidence comes from preclinical experiments in animals, and human-trial reports of topical opioids thus far have consisted of anecdotal cases or small, largely underpowered, studies.

Unresolved Questions
Clearly, more research is warranted and there are still questions needing more complete answers:
> What is the most efficacious opioid and/or combination of ingredients and their dosages?
> What is the most advantageous carrier (eg, gel, cream, lotion, DMSO, etc.) and method of application?
> Which pain conditions are most amenable to topical opioid therapy?
> What degree and duration of analgesic effects might be expected?
> In which circumstances could topical opioids completely replace the need for systemic opioids or other analgesics?
> What is the potential, if any, for developing tolerance or hyperalgesia during prolonged use of topical opioids?

There also is the question of whether systemic infiltration of topically applied opioids is completely avoided. The extremely low incidence of tolerance and side effects reported in animal studies with topical opioids has suggested that there is no systemic absorption [Watterson et al. 2004]. In early studies, Tennant et al. [1993] observed no detectable serum morphine in patients applying a topical morphine mixture daily for back pain, but more recently Tennant [2010A] has suggested that some patients regularly using topical opioid preparations covering large areas may show low levels of the opioid in serum and/or urine. In one case, a woman topically applying the equivalent of 60 mg morphine/day had trace amounts of 5 ng/mL in serum and 60 ng/mL in urine.

In a very small sample of human subjects with chronic arthritis (n=3), Wilken et al. [2005] reported good pain relief with the application of topical morphine; however, 24-hour urine collection did show the presence of systemic morphine. They concluded that, while topical morphine is absorbed to some extent systemically in the body, the degree of such absorption could not be quantified. Others have reported that opioid actions are restricted to the area of application without central, systemic effects [Jacobsen 2010, Joris et al. 1987]. Therefore, it appears that, even when it is possible to detect the presence of topically applied opioids in serum or urine, this is not tantamount to their producing adverse reactions due to centrally acting, systemic effects.

Many Benefits With Few, If Any, Risks
Despite the limited evidence — especially a lack of a large, well-designed clinical trials — the application of topical opioids for acute and chronic pain conditions of many types appears to represent a therapeutic option with unrecognized potential. Several promising benefits of topical opioids may be summarized as follows [adapted from Tennant 2010A]:
  1. They are relatively inexpensive; however, costs may vary and the mixtures must be specially compounded.

  2. Topical opioids have a favorable safety profile; side effects, if any, are relatively rare.

  3. Pain control is possible in localized areas, at and near the point of application, without adverse systemic effects.

  4. Patients are afforded greater self-control over pain relief, which can be psychologically beneficial.

  5. At the least, patients may be able to reduce consumption of systemic, oral or parenteral opioids.

  6. Hepatic metabolism is not required, which can be important in patients with compromised liver function or genetic deficiencies in metabolic enzymes.

  7. There is little, if any, potential for abuse and addiction.
The last point is important because the scant, if any, systemic effects of topical opioids (including psychotropic effects) and the extreme difficulty of extracting the opioid ingredient from a topical formulation, make it enormously unlikely that these analgesics would be abused or have any “street value” — with the possible exception of topical oral-rinse solutions. There would appear to be no overdose potential in adults with topical opioids.

Therefore, topical opioids also might be a safe and effective analgesic alternative for patients with moderate-to-severe acute or chronic pain who are at the highest risk of misusing or abusing oral opioids, including those who are concurrently abusing alcohol, benzodiazepines, or other drugs. And, with concerns these days about opioid misuse, abuse, and diversion, topical opioids would appear to be the ultimate “abuse deterrent” (indeed, “abuse avoidant”) formulation for helping to minimize the problems.

The application of topical opioids is an area of pain medicine amenable to creative pharmacotherapy unlike any other, considering the many possible combinations of ingredients that may be efficacious. The limited research suggests that, in combination with select opioids, a variety other ingredients might be added to topical formulations for greater pain relief, such as NSAIDs, low-dose naloxone, ketamine, lidocaine, and other ingredients; perhaps, even topical vitamin D. And, most compounding pharmacies offer a selection of a topical transdermal creams, gels, or other carrier mediums (possibly incorporating DMSO).

Currently, the prescribing of topical opioids for various pain conditions appears to be the purview of a select cadre of pain specialists who are aware of their potential and willing to experiment. Unfortunately, costs for these custom-compounded preparations are rarely, if ever, covered by healthcare insurance and this may be a barrier for many patients. Yet, it is curious that discussions of topical opioids have been largely overlooked or ignored by almost all medical publications.

It also is perplexing that, by all indications, pharmaceutical firms have not shown any interest in researching and developing proprietary topical opioid preparations. And, in lieu of such commercial support, why have government agencies withheld research funding to aggressively pursue this innovative approach for better pain care?

We encourage readers to comment below and share their own experiences with topical opioids.

Disclaimer: The above discussion is based on the evidence cited and is for informational purposes. It is not intended to offer medical guidance for treating specific health conditions. Furthermore, Pain Treatment Topics does not endorse or promote the off-label application of any drugs. In all cases, professional discretion is advised.

> Jacobsen J. Topical Opioids for Pain [Fast Facts and Concepts #185]. EPERC [End of Life / Palliative Education Resource Center], Medical College of Wisconsin. 2010 (update) [
article available here]
> Joris JL, Dubner R, Hargreaves KM. Opioid Analgesia at Peripheral Sites: A Target for Opioids Released During Stress and Inflammation. Anesth Analgesia. 1987;66(12):1277-1281 [
> Kolesnikov YA, Chereshnev I, Pasternak GW. Analgesic Synergy Between Topical Lidocaine and Topical Opioids. J Pharmacol Exper Ther. 2000;295(2):546-551 [
article here].
> Moody ML. Topical Medications in the Treatment of Pain. Pain Med News. 2010(Dec);8(12):15-21 [
article PDF here].
> Moore RA, Derry S, McQuay HJ. Topical Analgesics for Acute and Chronic Pain in Adults (Protocol). Cochrane Library. 2010;7(art. no. CD008609) [
access with subscription].
> Ney MJ. [Letter to the Editor.] Practical Pain Management. 2010(Nov/Dec);10(9):10 [no abstract].
> Schramm CL, Honda CN. Co-administration of Delta- and Mu-Opioid Receptor Agonists Promotes Peripheral Opioid Receptor Function. Pain. 2010;151(3):763-770 [
> Stein C. The Control of Pain in Peripheral Tissue by Opioids. New Eng J Med. 1995;332(25):1685-1690 [
article PDF here].
> Tandon OP, Mehta AK, Halder S, et al. Peripheral Interaction of Opioids and NMDA Receptors in Inflammatory Pain in Rats. Indian J Physiol Pharmacol. 2010;54(1):21-31 [
> Tennant F, Moll D, DePaulo V. Topical Morphine for Peripheral Pain [letter]. The Lancet. 1993;342(8878):1047-1048 [no abstract].
> Tennant F. Taking Advantage of the Peripheral Opioid Receptor. Practical Pain Management. 2010A;10(3):28-30 [
> Tennant F [2010B]. Use and Benefits of Topical Opioids by Intractable Pain Patients. Poster presented at 21st Annual Clinical Meeting of the American Academy of Pain Management; September 21-24, 2010; Las Vegas, Nevada. Poster #33 [no abstract].
> Watterson G, Howard R, Goldman A. Peripheral Opioids in Inflammatory Pain. Arch Dis Child. 2004;89:679-681 [
article here].
> Wilken M, Ineck JR, Rule AM. Chronic Arthritis Pain Management with Topical Morphine. J Pain Pall Care Pharmacother. 2005;19(4):39-44