Compounded Ketamine
A Useful Agent for Neuropathic Pain
Neal S Taub, M.D.
Patients often suffer with continued neuropathic pain even after the
typical medications have been prescribed. Prescribers can consider
topical agents as an alternative in the analgesic regimen. While the
more common topical analgesics include capsaicin and lidocaine, other
medications can provide different types of analgesic activity such as
excitatory mediators, peripheral afferents, and inhibitory influences.
Topical analgesics have many advantages over systemically
administered medications. The reduction or elimination of side-effects
stands chief among these advantages. Topical analgesics differ from
transdermal delivery methods in that prescribers use topical applications
to deliver local, rather than systemic, effects. Our practice, The Center
for Musculoskeletal & Pain Medicine, uses a variety of customcompounded agents to improve your patients’ experience with pain.
One of the custom compounds useful for some patients is a topical
ketamine cream. Peripheral N-methyl-D-aspartate (NMDA) receptors
have been implicated in nociception.1-3 Ketamine blocks NMDA and
5HT receptors, Na+ and Ca+ channels, and the edema response
associated with inflammation. Topical ketamine applications have
documented success with neuropathic pain in terms of providing some
direct analgesia and in terms of inhibiting sympathetically maintained
pain. However, the most important use of custom-compounded
ketamine cream is the reduction of hyperalgesia (an exaggerated
sensation after a painful stimulus), the reduction of allodynia (a painful
sensation elicited by a nonpainful stimulus), and as a toleranceprotective agent.4-12 The literature describes topical ketamine
applications as being useful for pain management in cases of postsurgical neuropathic pain, complex regional pain syndrome, lumbar
radiculopathy, post-herpetic neuralgia, and idiopathic proctodynia.
In 2006, Poyhai and Vainio proposed that ketamine cream worked by
being absorbed into the bloodstream and reducing central
sensitization.7 However, the evidence collected by Finch and colleagues
(Pain 2009), suggests that ketamine cream acts only locally.4 After
applying a 10% ketamine cream compound, they could not find
evidence of ketamine in the bloodstream for 20 patients, and ketamine
applied to healthy limbs produced no effect in painful limbs. Customcompounded ketamine creams have no documented side effects.
We introduce the subject of custom-compounded topical ketamine as an
illustration of the many considerations and possibilities available in pain
management.
References
1. Chizh B, Headley P, NMDA antagonists and neuropathic pain:
multiple drug targets and multiple uses. Curr Pharm Des 2005;
23: 2977-94.
2. Trist D. Excitatory amino acid agonists and antagonists:
pharmacology and therapeutic applications. Pharm Acta Helv
2000; 74: 221-9.
3. Sang C. NMDA-receptor antagonists in neuropathic pain:
experimental methods to clinical trials. J Pain Symptom Manage.
2000; 19: S21-S25.
4. Finch P, Knudsen L, Drummond P. Reduction of allodynia in
patients with complex regional pain syndrome: A double-blind,
placebo-controlled trial of topical ketamine. Pain. Nov 2009; 146
(1-2): 18-25.
5. Lehman J, Sciallis G. Effective use of topical amitriptyline
hydrochloride 2.5% and ketamine hydrochloride 0.5% for
analgesia in refractory proctodynia. J Drugs Dermatol. 2008; 7 (9):
8887-9.
6. Visser E, Schug S. The role of ketamine in pain management.
Biomed Pharmacother. 2006; 60: 341-348.
7. Poyhia R, Vainio A. Topically administered ketamine recduces
capsaicin-evoked mechanical hyperalgesia. Clin J Pain. 2006; 22
(1): 32-6.
8. Ushida T, Tani T, Kanbara T, et al. Analgesic effects of ketamine
ointment in patients with complex regional pain syndrome type 1.
Reg Anesth Pain Med. 2002; 27(5): 524-8.
9. Gammaitoni A, Gallagher R, Welz-Bosna M. Topical ketamine gel:
possible role in treating neuropathic pain. Pain Med. 2000; 1(1):
97-100.
10.
Warncke T, Jorum E, Stubhaug A. Local treatment with Nmethyl-D-aspartate receptor antagonist ketamine, inhibits
development of secondary hyperalgesia in mang by a peripheral
action. Neurosci Lett. 1997; 227:1-4.
11.
Pederson J, Galle T, Kehlet H. Peripheral analgesic
effectsof ketamine in acute inflammatory pain. 1998; 89: 58-66.
12.
Crowley K, Flores J, Hughes C, et al. Clinical application of
ketamine ointment in the treatment of sympathetically maintained
pain. Int J Pharmaceut Compound. 1998; 2: 122-127.
Compounded Drug Delivery for Analagesia, and Inflammation.
Michele Koukhab, Doctor of Pharmacy Program
USC School of Pharmacy, Class of 2007
INTRODUCTION
Among the latest innovations of the pharmaceutical industry is the technology of drug delivery that
overcomes the disadvantages of oral drug administration. These effects include first-pass metabolism and
1
adverse drug side effects. An alternate route of administration that bypasses these events would offer the
patient an improved substitute to conventional therapy, and would also allow for longer treatment intervals.
The non-steroidal anti-inflammatory drugs (NSAIDs) have proven to be effective in the treatment of soft
2
tissue injuries; such as sprains, strains, and contusions. They are widely used as analgesics, and in the
1
treatment of locomotor pathologies and local inflammation . Oral NSAIDs are often adjuncts to treatment
but can cause the serious systemic side effects of peptic ulcer and gastrointestinal hemorrhage, especially
2
after long term use.
Applied topically, these drugs are formulated to penetrate the skin, subcutaneous fatty tissue, and muscle in
amounts sufficient to exert local therapeutic effects, without reaching higher plasma drug concentrations.
Therefore, NSAIDs offer the advantage of local, enhanced drug delivery to affected tissues with a reduced
incidence of systemic adverse events.
A case-controlled study demonstrated that when adjustments were made for the confounding effects of
concurrent oral NSAID use, topical NSAID administration was not significantly associated with upper
gastrointestinal bleeding or perforation. The study also showed that the topical dosage was well tolerated
and had clinically significant, less adverse events. Furthermore, it was found that the use of topical NSAID
in soft tissue injury (tendonitis and sprain) resulted in more rapid healing (compared with no intervention).
2
KETOPROFEN
Ketoprofen is a potent NSAID that is widely used in clinical practice for the control of acute and
chronic pain of soft tissues and skeletal muscle system. The importance of ketoprofen in the therapeutic
field has stimulated the development of topical dosage forms to improve its percutaneous absorption
through the application site. Moreover topical dosage forms could provide relatively consistent drug levels
for prolonged periods and avoid gastric irritation, as well as the other typical side effects of oral NSAID
3
administration.
Ketoprofen belongs to the group of substituted 2-phenylproprionic acids which has analgesic, antiinflammatory and antipyretic effects. Ketoprofen exerts the majority of its analgesic actions through
inhibition of the synthesis of prostaglandins by inhibiting the enzyme cyclooxygenase. Ketoprofen has also
been shown to stabilize lysosomal membranes, inhibit leukotriene synthesis through inhibition of
lipoxygenase, exhibit anti-bradykinin activity and scavenge hydroxyl radicals, any of which may contribute
4
to the peripheral analgesic effects of ketoprofen.
A study performed by Alarcon, et al, comparing the topical penetration of various NSAIDS (ketoprofen,
ketorlac, indomethacin, etc), found that Ketoprofen had the best permeating ability within its class.
1 Other
studies have found that topical formulations of ketoprofen demonstrate effectiveness for the treatment of well-localized soft-tissue injury and joint pain, as well as
being effective in reducing muscle soreness after repetitive muscle contraction. These studies also demonstrate the maintenance of a low
5, 6.
rate and extent of
systemic absorption with no reported adverse events.
Transdermal ketoprofen has a relatively fast onset of action, being able to suppress pain ratings by 51% in
patients within an hour of application, when compared with placebo.
Copyright protected, Living Well Pharmacy Inc. 2005 1
4
GABAPENTIN
Gabapentin, a second-generation anti-epileptic drug, appears to have some beneficial effects on post-spinal
cord injury pain. Agents that reduce hyperexcitability (by blocking sodium and/or glutamate channels) may
7
reduce central pain symptoms. Analgesic action of gabapentin is mainly mediated by actions on the spinal
8
cord.
Gabapentin is useful in the treatment of neuralgia in all areas of the body. Its positive effect on neuralgia
includes trigeminal neuralgia, glossopharyngeal neuralgia refractory to the usual medical treatments, and
facial neuritis. Neuropathy can also be treated with gabapentin. Gabapentin is effective in the treatment of
human immunodeficiency virus (HIV) neuropathy, and painful diabetic neuropathy. It is also useful in
treating inflammatory pain.
9
8
Gabapentin is effective in the treatment of acute herpetic pain without apparent adverse effects. These
roles have been confirmed in reviews of controlled studies.
Gabapentin was the first anticonvulsant with proven benefit in post-herpetic neuralgia. A randomized,
double-blind study comparing gabapentin to placebo showed reduced pain and sleep interference, and
improved mood and quality of life. Minor adverse events were reported and included somnolence,
10
dizziness, ataxia and peripheral edema.
Although its side effect profile is mild, the occurrence of adverse events could be minimized with
transdermal use. Gabapentin has induced cholestasis, hepatotoxicity, anorgasmia in women, and has also
been associated with dyskinesia. It should be used with caution in myasthenia gravis. It does not seem to
interact with warfarin.
9
LIDOCAINE
Local anesthetics such as lidocaine prevent transmission of nerve impulses by inhibiting passage
11
of sodium ions through ion-selective sodium channels in nerve membranes. Systemic absorption remains
minimal, with the highest recorded concentrations remaining at an order of magnitude below the minimum
anti-arrhythmic levels. Lidocaine is well tolerated with few systemic adverse events and may provide
beneficial pain relief for patients receiving multidisciplinary treatment without increasing risks for adverse
12
drug interactions.
Transdermal lidocaine has been shown clinically to reduce pain associated with post-herpetic neuralgia and
12
back injury. Lidocaine is effective for the significant reduction in the intensity of commonly reported
pain qualities in patients with neuropathic and non-neuropathic chronic pain due to low-back pain,
osteoarthritis, post-herpetic neuralgia, and painful diabetic neuropathy.
13
KETAMINE
14
Ketamine hydrochloride is an NMDA receptor antagonist with opioid receptor activity that has
15
been useful for anesthesia and analgesia. It has been shown in clinical study that topical ketamine reduced
15, 16
pain in patients with no systemic side effects, indicating negligible or no generalized absorption.
Ketamine has been proposed recently for neuropathic pain secondary to its NMDA receptor activity. The
current application as a topical drug stems from the theory that ketamine has peripheral action at both
opioid and Na+-K+ channels.
17
14
Controlled studies and case reports on ketamine demonstrate efficacy in neuropathic and nociceptive pain.
Patients reported alterations in temperature sensation, feelings of relaxation and decreased tension in the
area of application, and pain relief. Reduction in numerical pain scores after application of ketamine ranged
17
from 53-100%. Patients who respond to ketamine tend to demonstrate dramatic pain relief that precludes
the desire to stop treatment due to psychotomimetic effects. Ketamine also has been reported to produce
opioid dose sparing and good patient acceptance.
14
No significant side effects were reported with topical ketamine. Topical ketamine may provide clinicians
17
with a new option in the battle against chronic neuropathic pain , especially in patients who have been
refractory to standard analgesic medication regimens.
Copyright protected, Living Well Pharmacy Inc. 2005 2
14
References
1. Alarcon, L, Escnbano, E, et al, A comparative study of the transdermal penetration of a series of nonsteroidal
anti-inflammatory drugs, Journal of Pharmaceutical Sciences, 2002, 86 (24) 503-308
2. Mazieres, B, Rouanet, S, Velicy, J; Topical Ketoprofen Patch (100 mg) for the treatment of Ankle Sprain, a
randomized, double-blind, placebo-controlled study; American Journal of Sports Medicine, 2005, 33 (4) 515524
3. Moretti, MD, Gavini, E, Peana, AT; In vitro release and antiinflammatory activity of topical
formulations of ketoprofen; Bollettino Chimico Farmaceutico; 2000, 139(2):67-72
4. Steen KH, Wegner H, Meller ST; Analgesic profile of peroral and topical ketoprofen upon low pH-
induced muscle pain; Pain; 2001, 93 (1) 23-33
5. Dowling, T, Arjomand, M, Lin, E; Relative bioavailability of ketoprofen 20% in a poloxamer-
lecithin organogel; AJSHP, 2004, 61(23) 2541-2544
6. Cannavino, C, Abrams, et al; Efficacy of transdermal ketoprofen for delayed onset muscle soreness;
Clinical Journal of Sport Medicine, 2003. 13(4) 200-208
7. Nicholson, B; Diagnosis and management of neuropathic pain: a balanced approach to treatment;
Journal of the American Academy of Nurse Practitioners; 2003, 15(12):3-9
8. Takasaki, I, Andoh, T, et al; Gabapentin antinociception in mice with acute herpetic pain induced by
herpes simplex virus infection; Journal of Pharmacology and Experimental Therapeutics; 2001,
296(2) 270-5
9. Scheinfeld, N; The role of gabapentin in treating diseases with cutaneous manifestations and pain;
International Journal of Dermatology; 2003, 42 (6) 491-5
10. Douglas, M, Johnson, R, Cunningham, A; Tolerability of Treatments for Post Herpetic Neuralgia;
Drug Safety; 2004, 27 (15) 1217-1233.
11. Liem, E, Joiner, T, Tsueda, K; Increased sensitivity to thermal pain and reduced subcutaneous
lidocaine efficacy in redheads; Anesthesiology; 2005, 102(3) 509-514
12. Rowbotham, M, Galer B, et al; Topical lidocaine patch relieves postherpetic neuralgia more
effectively than a vehicle topical patch: results of an enriched enrollment study; Pain; 1999, 80 (3)
533-538
13. Argoff, C; Conclusions: chronic pain studies of lidocaine patch 5% using the Neuropathic Pain
Scale; Current Medical Research & Opinion; 2004, 20 (2) S29-31
14. Kronenberg, R; Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and
intranasal administration; Journal of Pain & Palliative Care Pharmacotherapy; 2002, 16 (3) 27-35
15. Csoka, I, Csanyi, E, et al; In vitro and in vivo percutaneous absorption of topical dosage forms:
case studies; International Journal of Pharmaceutics; 2005, 291, 11-19
16. Quan, M, Wellish, Gilden, D; Topical ketamine treatment of postherpetic neuralgia; Neurology;
2003, 60, 1391–1392
17. Gammaitoni, A, Gallagher, R, Welz-Bonsa, M; Topical Ketamine Gel: Possible Role in Treating
Neuropathic; Pain Medicine; 2000, 1 (4) 97-100