Anesthesia & Analgesia:
Pain Medicine: Review Article
Topical and Peripheral Ketamine as an Analgesic
Sawynok, Jana PhD
From the Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Accepted for publication January 16, 2014.
Funding: No funding related to this article.
Conflicts of Interest: See Disclosures at the end of the article.
Reprints will not be available from the author.
Address correspondence to Jana Sawynok, PhD, Department of Pharmacology, Dalhousie University, P.O. Box 15000, Halifax, Nova Scotia, B3H 4R2. Address e-mail to firstname.lastname@example.org.
Ketamine, in subanesthetic doses, produces systemic analgesia in chronic pain settings, an action largely attributed to block of N-methyl-D-aspartate receptors in the spinal cord and inhibition of central sensitization processes. N-methyl-D-aspartate receptors also are located peripherally on sensory afferent nerve endings, and this provided the initial impetus for exploring peripheral applications of ketamine. Ketamine also produces several other pharmacological actions (block of ion channels and receptors, modulation of transporters, anti-inflammatory effects), and while these may require higher concentrations, after topical (e.g., as gels, creams) and peripheral application (e.g., localized injections), local tissue concentrations are higher than those after systemic administration and can engage lower affinity mechanisms. Peripheral administration of ketamine by localized injection produced some alterations in sensory thresholds in experimental trials in volunteers and in complex regional pain syndrome subjects in experimental settings, but many variables were unaltered. There are several case reports of analgesia after topical application of ketamine given alone in neuropathic pain, but controlled trials have not confirmed such effects. A combination of topical ketamine with several other agents produced pain relief in case, and case series, reports with response rates of 40% to 75% in retrospective analyses. In controlled trials of neuropathic pain with topical ketamine combinations, there were improvements in some outcomes, but optimal dosing and drug combinations were not clear. Given orally (as a gargle, throat swab, localized peritonsillar injections), ketamine produced significant oral/throat analgesia in controlled trials in postoperative settings. Topical analgesics are likely more effective in particular conditions (patient factors, disease factors), and future trials of topical ketamine should include a consideration of factors that could predispose to favorable outcomes.
Ketamine was synthesized in the early 1960s as part of the search for an ideal anesthetic, and introduced into clinical medicine as a dissociative anesthetic in 1965.1,2 As a general anesthetic, it provides cardiac stability but is limited by psychotropic and other central effects. In the early 1980s, ketamine was recognized to block glutamate N-methyl-D-aspartate (NMDA) receptors,3 which were emerging as important contributors to central sensitization within the spinal cord and to chronic pain.4 By 2000, a literature search identified 378 animal studies and 132 human studies that had evaluated NMDA receptors in pain and provided convincing evidence for a role of these receptors in chronic pain states.5 A 2003 review on the use of ketamine for management of chronic pain in clinical populations reported 11 controlled trials and many uncontrolled trials and case reports6; subsequent reviews published in 2009 to 2010 extended the number of controlled trials to 22–297,8 and 36.9 Most trials have examined effects of IV boluses and infusions, subcutaneous (SC) or IM injections, and oral ketamine. Three trials have evaluated the efficacy of long-term IV infusions of ketamine (4–5 hours daily for 7–10 days or continuously over 4 days) and demonstrated promising long-term effects.9 Paralleling this clinical development, the pharmacology of low-dose ketamine in relation to analgesia has continued to be explored on a mechanistic basis.10,11 As the molecular biology of the NMDA receptor has become better understood, there also has been a focus on development of novel NMDA receptor blocking drugs, both for chronic pain and other conditions involving central nervous system dysfunction.12,13
Since the mid-1990s, it was recognized that glutamate receptors are located on peripheral nerve endings and can contribute to pain signaling.14,15 Key observations include: (1) glutamate is present within sensory nerve endings and is released extracellularly by noxious stimulation; (2) NMDA and other glutamate receptors are present on sensory nerve endings, and on cells adjacent to nerve endings (e.g., keratinocytes, immune cells); (3) inflammation and tissue damage cause elevated glutamate release from primary afferent nerve endings and keratinocytes; and (4) peripheral applications of glutamate receptor agonists lead to activation of sensory nerves, with electrophysiological and behavioral manifestations.14,15 In accord with these developments, there has been an emerging interest in the potential for NMDA receptor antagonists to be applied topically, or peripherally by other means, to represent a novel strategy for pain management. Clinical case reports of the efficacy of topical ketamine for relieving pain began to appear in the late 1990s.16,17 Topical approaches to analgesia have the potential to produce pain relief with minimal adverse systemic effects due to low plasma levels, and, as mechanisms involved in peripheral pain signaling have come to be better understood, there has been considerable interest in exploration of novel topical agents as analgesics.18,19
The purpose of this review is: (1) to consider mechanisms potentially involved in peripheral actions of ketamine; (2) to summarize clinical studies using topical and peripheral ketamine for pain management; and (3) to identify areas for further development. In constructing the review, standard methodologies using keyword searches relevant to particular sections and attentive reading of the literature were used; this is not a systematic review, and is best characterized as a narrative and interpretive review.
PERIPHERAL MECHANISMS OF ACTION OF KETAMINE
Plasma concentrations associated with analgesic actions of ketamine in humans are in the low micromolar range (0.3–1.0 μM, 100–300 ng/mL) and are consistent with concentrations that block NMDA receptors; this has provided the main foundation for understanding the pharmacology of ketamine as a systemic analgesic drug.5,11,20 During the 1990s, additional pharmacological actions produced by ketamine were recognized, and their potential contributions to analgesia considered.21–23 However, many of these actions occur at higher concentrations (10–100 μM and beyond) and were not considered to account for systemic analgesia that occurs with low doses of ketamine.5,11,20 Additional actions of ketamine are summarized in Table 1. These include: (1) binding to multiple opioid receptors (ORs)24; (2) binding to monoamine transporters23,25; (3) binding to muscarinic and nicotinic cholinergic receptors and inhibition of function23; (4) binding to D2 and 5-HT2 receptors26; (5) inhibition of ion channels (Na+, Ca2+, K+)20–22,27,28; (6) decreased activation and migration of microglia.28 Additional actions of ketamine seen at higher concentrations were suggested to contribute to the pharmacological profile of ketamine at higher systemic doses in preclinical studies, high and near-anesthetic doses in humans,11 and after spinal administration.27 When ketamine is administered topically or injected locally into tissue, higher local tissue concentrations may occur compared with systemic dosing, and lower affinity actions also may contribute to the pharmacology of peripheral ketamine. Thus, 0.5% to 5.0% ketamine (Tables 2 and 3) is 5 to 50 mg/mL and is a solution of approximately 18 to 180 mM, while 0.5 mg/kg in 2 mL injected locally (peritonsillar)29,30 is a solution of approximately 30 mM. These solutions undergo dilution after dermal penetration and tissue distribution after topical applications, or tissue distribution and systemic absorption after localized injections. Although tissue concentrations after such applications have not been assessed directly, it is conceivable that local concentrations are within ranges that can recruit several lower affinity mechanisms of action of ketamine noted above. In direct mechanistic studies, when a drug action is to recruit a mechanism, antagonists can provide direct evidence for involvement of that mechanism; however, when a drug action is to interfere with that mechanism, it is more difficult to definitively implicate that mechanism because mimicry by agents that clearly engage that mechanism provide necessary, but not sufficient, information to implicate that mechanism. Few preclinical studies have directly addressed mechanisms involved in peripheral antinociception by ketamine, but some recent studies have implicated the nitric oxide/cyclic guanosine monophosphate pathways and adenosine triphosphate-sensitive K+ channels in such actions.31,32
Many of the above mechanisms primarily have been considered in relation to neuronal sites of action with implications for influencing pain signaling in the periphery via actions on nociceptors. It is now appreciated that keratinocytes in the epidermis can contribute to pain signaling via interactions with nerve endings and that these undergo changes after inflammation and injury.33–35 Keratinocytes express NMDA receptors and release L-glutamate in the epidermis, and these play a role in the differentiation of keratinocytes.36–39 Given the tissue plasticity involving keratinocytes that occurs after injury and in disease states, a potential role for actions of ketamine at NMDA receptors on keratinocytes, as well as via other mechanisms, is feasible.
A further set of actions that contribute to the pharmacological profile of ketamine is regulation of inflammatory and immune responses both in vitro and in vivo, which leads to decreased levels of several proinflammatory mediators (e.g., interleukin-1β, interleukin-6, interleukin-8, tumor necrosis factor-α).40,41 These actions result from ketamine interacting with toll-like receptors on immune cells and repression of nuclear factors (NF-κB, AP-1). A clinical correlation to this anti-inflammatory effect is that ketamine inhibits early postoperative inflammatory responses42; the functional consequences of this are not clear but could involve reduction in postoperative adverse effects (e.g., cognitive dysfunction).43 With respect to peripheral actions of ketamine, nebulized ketamine delivered directly to the airways resulted in suppression of allergen-mediated airway hyperreactivity, reduction in airway inflammation and inflammatory cell infiltration, and decreased levels of inflammatory mediators in airway lavage in a model of allergen-induced asthma in rats.44 These peripheral anti-inflammatory actions of ketamine could contribute to the peripheral analgesic actions of ketamine in several clinical settings. For example, complex regional pain syndrome (CRPS) type 1 involves several mechanisms, including peripheral inflammation, peripheral vascular changes, and peripheral hypersensitivity,45,46 and ketamine’s actions on inflammatory processes, as well as on neurons, keratinocytes, and other cell types, could account for unique actions in this condition (Table 2).
PERIPHERAL ADMINISTRATION OF KETAMINE IN EXPERIMENTAL TRIALS
Reports that peripheral NMDA receptors contribute to pain signaling in preclinical models47–49 stimulated experimental studies whereby ketamine was administered locally by acute SC injection. In rodents, peripheral delivery of ketamine was reported to produce antinociception in the formalin test,50 in a thermal hyperalgesia model,51 and a prostaglandin E2-hyperalgesia model.31,32 In humans, Warncke et al.52 demonstrated that SC ketamine 5 mg reduced primary hyperalgesia and development of secondary hyperalgesia after thermal injury in healthy volunteers. Pedersen et al.53 reported a transient reduction in heat and mechanical thresholds immediately after injection of SC ketamine 7.5 mg but no effect at other times or on secondary hyperalgesia in healthy volunteers. In the intradermal capsaicin (10 μg)-induced hyperalgesia model in humans, SC ketamine 1 mg had no effect on transient pain but inhibited secondary hyperalgesia; it also increased mechanical thresholds when given in the absence of capsaicin; a dose of 0.1 mg ketamine had no such effects.54 In other such studies, SC injection of 5 mg ketamine had no effect on either transient pain or secondary hyperalgesia in response to capsaicin 100 μg55,56; the difference in results was perhaps due to use of a higher capsaicin dose in the latter studies. In each of these studies, ketamine consistently inhibited the vascular flare response (axon reflex) to capsaicin, indicating involvement of different mechanisms in such responses compared with pain.54–56 Side effects consistent with systemic effects (central actions) were reported after SC injections of 5 mg ketamine (in 25%)53 and 7.5 mg ketamine (in 67%).55 Local injection of 6 mg ketamine SC (0.3%, 2 mL) produced local anesthetic actions to von Frey filament testing in volunteers; this action was proposed to account for enhancement of analgesia by other local anesthetic drugs.57
Ketamine has also been administered topically as a gel in humans, and acute sensory effects determined. In healthy volunteers, topical ketamine (1 mL of 50 mg/mL, 5%) had no effect on the immediate burning response to capsaicin 250 μg but reduced mechanical hyperalgesia over 1 hour.58 The same response was seen with topical application of ketamine to the other side of the body, and the effect was attributed to a systemic action.58 Another study examined topical ketamine (0.5 mL of 10%, 50 mg) in patients with CRPS59 and reported reduction in allodynia and punctate responses on the symptomatic side 30 minutes after application of topical ketamine; this was due to a local action because application to the healthy limb had no such effect. The latter study also examined plasma levels of ketamine and norketamine after topical administration (blood sampled 1 hour after administration) and reported no detectable plasma levels (limit 0.5–0.7 ng/mL).59 Plasma levels of 150 ng/mL are needed for analgesia after IV or IM administration of ketamine.60–63 It is not clear why one study implicated systemic58 while the other implicated local ketamine actions,59 because both used the same dose and vehicle; whether tissue conditions encountered in CRPS influence skin absorption and local tissue distribution compared with healthy volunteers remains to be determined.
TOPICAL KETAMINE FOR NEUROPATHIC PAIN
Neuropathic pain results from injury (lesion, disease) to the somatosensory system and can involve peripheral and central sites; manifestations include spontaneous (paresthesia, pain), negative (hypoesthesia, hypoalgesia), and positive (allodynia, hyperalgesia) sensory symptoms.64 Mechanisms involved in neuropathic pain occur at multiple levels of the pain neuraxis and include peripheral sensitization, central sensitization in the spinal cord, and central changes.65 Several classes of analgesics exhibit efficacy in neuropathic pain (antidepressants, anticonvulsants, opioids, other adjuvants), but oral treatments exhibit partial efficacy and can be limited by adverse effects.66,67 Two topical analgesics are approved for use in neuropathic pain, lidocaine medicated plaster,68 and the high-concentration capsaicin patch,69 indicating the usefulness of this approach for such conditions.
Since 1998, with publication of several cases reporting efficacy of topical ketamine for neuropathic pain,16 additional cases and case series reports have been published (Table 2, 2A). These describe cases of sympathetically maintained pain, reflex-sympathetic dystrophy, CRPS, postherpetic neuralgia, and other conditions.17,70–72 The amount of ketamine applied varied, with concentrations ranging mostly from 0.5% to 5.0% (applications of 1–2 mL, 2–4 × day). Several controlled trials have compared topical ketamine with placebo groups in clinical populations (Table 2, 2B). Ketamine 0.5% to 1.0% had no effect compared with placebo over 2 days,73 2 weeks,74 or 3 weeks75 in several neuropathic pain conditions. Furthermore, ketamine 5% had no effect on painful diabetic neuropathy over 4 weeks.76 These controlled trials of topical ketamine do not generally recapitulate case report observations. In an experimental trial in CRPS subjects, acute application of topical ketamine 10% had no effect on spontaneous pain, but reduced evoked sensory thresholds 30 minutes after application.59 This trial differed from other efficacy trials in that it determined effects of acute applications rather than chronic applications for condition-related pain. Neither topical application of ketamine 0.5% to 1% (daily)73,75 nor 10% (acute application)59 produced detectable levels of ketamine or the active metabolite, norketamine, in plasma. There are no data on plasma ketamine levels after repeated doses of higher concentrations of ketamine (5%–10%).
TOPICAL KETAMINE IN COMBINATION WITH OTHER DRUGS FOR NEUROPATHIC PAIN
There are several controlled trials of topical ketamine administered in combination with other drugs for neuropathic pain (Table 3, 3A). When compared with placebo, topical ketamine 0.5% + amitriptyline 1% had no effect on mixed neuropathic pain over 2 days,73 and topical ketamine 1% + amitriptyline 2% had no effect over 3 weeks.75 In an open-label study over 12 months, pain was reduced 34% to 47% with this topical combination.77 In a dose-range comparison of ketamine + amitriptyline (1%/2%, 2%/4%), only the higher combination produced a significant reduction in pain compared with placebo.78,79 When ketamine 1.5% + amitriptyline 3% + baclofen 0.8% was compared with placebo for chemotherapy-induced neuropathy, there was a significant improvement in motor subscales and a trend toward improvement in sensory effects.80 When ketamine 1% + amitriptyline 2% was evaluated in an open-label trial for radiation skin reactions, there were acute reductions in several measures of pain at 30 minutes and reductions in burning pain at 2 weeks.81
There are several case studies, including several case series reports, indicating the effects of topical ketamine in combination with other drugs (Table 3, 3B). Ketamine 0.5% + amitriptyline 1% produced marked improvements in pain and function in a case of erythromelalgia, a disorder characterized by redness, increased skin temperature and pain in the extremities that has vascular and neuropathic elements; a further 4 of 5 cases reported improvements in pain >50%.82 A subsequent retrospective analysis of 36 cases of erythromelalgia treated with topical ketamine + amitriptyline indicated 75% had some relief of symptoms.83 A report of successful treatment of proctodynia with ketamine 0.5% + amitriptyline 2.5%84 was followed by a retrospective analysis of 13 cases of rectal, genital, or perineal pain where 85% reported some relief of symptoms.85 Finally, a case of neuropathic itching relieved by ketamine 0.5% + amitriptyline 1%86 was followed by retrospective analysis of 16 cases; 62% had some relief from localized pruritis (including neuropathic) with topical regimens.87 Each of the retrospective analyses recognized inherent limitations to the approach; however, each noted a high response rate in conditions that are challenging to treat and encouraged further clinical exploration. Finally, there are several case reports of good outcomes with ketamine given in combination with several other ingredients for neuropathic pain. Thus, amitriptyline 5%, ketamine 10%, and dimethyl sulfoxide 50% (given sequentially in that order) produced stepwise improvements in CRPS;88 ketamine 10% along with oral palmitoylethanolamide relieved CRPS,89 and ketamine 10% along with lidocaine 8%, clonidine 0.2%, and ketoprofen 5% provided pain relief in postherpetic neuralgia.90 A retrospective survey of ketamine in combination with several other drugs indicates a response rate of 41% for orofacial pain,91 and when combined with lidocaine, 73% in cases of neuropathic pain.92
These case reports provide promising observations that suggest topical ketamine in combination with other drugs, and in particular with amitriptyline, is useful in cases of neuropathic pain. While controlled trials do not provide consistent data for efficacy, there may be a concentration–response relationship,78,79 and placebo-controlled trials generally have examined lower concentrations.73,75 Topical analgesics are not universally effective, and open-label trials of 5% lidocaine medicated plaster (which is approved for use) indicate response rates of 50% to 70%.93,94 Future controlled trials of topical analgesics will need to attend to factors that might predict responses to topical analgesics, such as pain or sensory characteristics, patient characteristics, and disease duration and severity.95 For example, post hoc analysis indicates catastrophizing can contribute to outcomes in topical analgesic trials, including formulations containing ketamine.96
TOPICAL AND LOCALIZED DELIVERY OF KETAMINE FOR ORAL INDICATIONS
After recognition of the peripheral effects of NMDA receptors on pain signaling, ketamine was administered orally as a mouthwash for oral pain. Thus, Slatkin and Rhiner97 reported a case of oral cancer and radiation-induced mucositis that was treated with ketamine oral rinse (20 mg/5 mL, swished for 1 minute then expectorated); this led to an immediate reduction in pain; with continued use over a week, pain was reproducibly reduced, and benefit lasted hours; the condition improved over several months with further use. Subsequently, ketamine gargle was explored for postoperative sore throat resulting from endotracheal intubation for surgery. There are now several placebo-controlled studies (N = 40–46 subjects) reporting ketamine gargle (40–50 mg/30 mL, for 30–40 seconds), given after arrival in the operating room before surgery, reduces postoperative sore throat scores 2 to 24 hours after surgery.98–101 Plasma levels of ketamine and norketamine were low, and the effect of the gargle was considered to be due to a local peripheral action.100
Ketamine also has been applied topically to the tonsillar fossa after tonsillectomy in children.102,103 In one trial, ketamine 20 mg (in 10 mL vehicle) was applied directly to the tonsillar fossa, after surgery and control of bleeding, and then aspirated after 5 minutes; ketamine (as well as morphine and ketamine + morphine) produced analgesia and reduced rescue medication intake over 24 hours after surgery compared with artificial saliva.102 In another trial, ketamine 20 mg (in 5 mL, soaked in a swab) was applied to the fossa for 5 minutes; this produced significant analgesic effects compared with placebo in the postsurgical interval.103 Both trials concluded topical ketamine seemed a safe, effective, and easy approach for decreasing tonsillectomy pain. Other studies used peritonsillar injections of ketamine (0.5–1 mg/kg, 2 mL) and reported lower pain after surgery, less postoperative dysphagia, and reduced analgesic use.29,30,104,105 Side effects were not observed after local injections of ketamine, and preincisional injection of ketamine into the tonsils was considered safe and effective for pain after tonsillectomy. In these latter studies, plasma levels of ketamine after local injections into tonsils were not determined. While outcomes might reflect systemic actions, a peripheral action also is likely in view of the effects of topical ketamine applications noted above, and postsurgical effects may well have resulted from both peripheral and central actions.
SUMMARY AND CONCLUSIONS
Ketamine, in anesthetic doses, produces dose-related unconsciousness and profound analgesia, but use is limited by adverse central nervous system effects (psychotropic effects, abuse liability). At subanesthetic doses, systemic ketamine produces analgesia, an action largely attributed to block of NMDA receptors in the spinal cord and inhibition of central sensitization (although other actions likely also contribute). Since the recognition of NMDA receptors on sensory afferent nerve endings in the mid-1990s, ketamine has been applied to the peripheral compartment as gels and creams at somatic cutaneous sites, and, more recently, as mouthwashes, gargles, swabs, or local injections for oral indications. When given peripherally, ketamine can achieve higher local tissue concentrations than when given systemically, and recruit more of the pharmacological actions that have been reported for ketamine; such actions include neuronal effects as well as actions on other cell types (keratinocytes, immune cells). The evidence supporting peripheral analgesic actions of topical ketamine given alone consists of case reports; controlled trials have not replicated those observations. Ketamine also has been administered topically in combination with other drugs (amitriptyline, baclofen, lidocaine, ketoprofen, clonidine, gabapentin). Controlled trials provide some data supporting efficacy, but optimal doses and drug combinations are not clear. Individual case reports indicate benefits in individuals that have often been refractory, and case series reports indicate a favorable rate of pain relief. When applied to the oral cavity, ketamine produced statistically significant benefits in pain measures in controlled trials. This collective body of information provides support for further clinical exploration of ketamine as a peripherally active analgesic when given alone in certain settings (especially oral indications) and as a topical analgesic in combination with other drugs for cutaneous somatic sites in neuropathic pain. Topical analgesics probably will be most effective in subpopulations of individuals, and it will be important to address factors (e.g., pain or sensory characteristics, patient characteristics, disease duration, and severity) that might better predict those who will respond to topical analgesics.
Name: Jana Sawynok, PhD.
Contribution: Sole contributor.
Conflicts of Interest: Author has received license fees from Epicept.
This manuscript was handled by: Spencer S. Liu, MD.
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