Analgesic Effects of Ketamine Ointment in Patients with Complex Regional Pain Syndrome Type 1

Case Reports Analgesic Effects of Ketamine Ointment in Patients With Complex Regional Pain Syndrome Type 1

Takahiro Ushida, M.D., Toshikazu Tani, M.D., Tetsuya Kanbara, M.D., Vadim S. Zinchuk, M.D., Motohiro Kawasaki, M.D., and Hiroshi Yamamoto, M.D.

Objective: Ketamine hydrochloride (KET), an agent used for general anesthesia, has local anesthetic effects and N-methyl-D-aspartate (NMDA) receptor antagonist action. Because recent studies emphasized the role of peripherally distributed NMDA receptors in processing the nociceptive information, we investigated whether peripheral application of the ointment containing KET is able to attenuate the symptoms of local neuropathic pain. Case Reports: We applied ointment containing KET (0.25%-1.5%) to the affected area on limbs in 5 patients with complex regional pain syndrome type I (CRPS I) and in 2 patients with type II (CRPS II). One to 2 weeks later, we observed improvement of the report of pain intensity, measured by the visual analog scale, in 4 patients with acute early dystrophic stage of CRPS I. Swelling of the affected limbs subsided as well. No apparent changes were noticed in 1 patient with chronic atrophic stage of CRPS I and in both patients with CRPS II. Conclusion: Topical application of KET appears to be beneﬁcial for the patients with acute early dystrophic stage of CRPS I because of either its local anesthetic effect or NMDA receptor antagonist action. Patients with chronic atrophic stage of CRPS I and CRPS II patients do not appear to respond to this treatment. Reg Anesth Pain Med 2002;27:524-528. Key Words: Allodynia, Analgesia, CRPS, Hyperalgesia, Neuropathic pain.

llodynia and hyperalgesia, abnormal pain role of these receptors in processing of pain and Asymptoms accompanying the complex re- report that antagonists of glutamate receptors are gional pain syndrome type I (CRPS I), are major effective.3-5 The N-methyl-D-aspartate (NMDA) re- findings of posttraumatic neuropathic pain. They ceptor, 1 of 3 identified ionotropic glutamate recep- are usually managed by sympathetic block or med- tor subtypes, is widely distributed throughout the ications, such as nonsteroidal anti-inflammatory central nervous system.6 In the spinal cord, NMDA drugs, anticonvulsants, and antidepressants.1 In receptors are involved in pain transmission and are some cases, however, this approach is not effective involved in allodynia and hyperalgesia. In animal enough, and other treatments are needed.2 models, NMDA receptors were found to be respon- Among the ways to control allodynia and hyper- sible for the formation of experimental neuropathic algesia in CRPS I patients is to use drugs that target pain.7,8 It is also reported that both intravenous and glutamate receptors. Numerous studies showed the oral administration of NMDA receptor antagonists attenuate neuropathic pain in humans.9,10 In addition to their central locations, recent mor- From the Departments of Orthopedic Surgery (T.U., T.T., M.K.), Anesthesiology (T.K.), and Anatomy and Cell Biology phologic and behavioral studies also found gluta- (V.S.Z), Kochi Medical School, Nankoku, Kochi, Japan. mate receptors, including the NMDA receptor, on Accepted for publication May 2, 2002. peripheral axons and terminals.11 Animal studies Reprint requests: Takahiro Ushida, M.D., Department of Or- 12-15 thopedic Surgery, Kochi Medical School, Kohasu, Nankoku, Ko- showed their role in nociceptive signaling. It chi 783-8505, Japan. E-mail: [email protected]. was also reported that experimentally induced in- © 2002 by the American Society of Regional Anesthesia and flammation in the periphery increases the number Pain Medicine. 16 1098-7339/02/2705-0017$35.00/0 of NMDA receptors on peripheral nerve fibers. In doi:10.1053/rapm.2002.35517 humans, intradermal and intravenous regional ad-

524 Regional Anesthesia and Pain Medicine, Vol 27, No 5 (September–October), 2002: pp 524–528 The Effect of Ketamine Ointment • Ushida et al. 525 ministration of ketamine hydrochloride (KET) pro- range of motion of the wrist and fingers was also duced a local anesthetic effect and attenuated burn- noticed. As a control, we applied the same ointment induced primary and secondary hyperalgesia.17-19 lacking KET for 1 week. No improvement was re- Taking all these findings into account, we examined ported by the patient during that period of time. whether application of KET ointment is of thera- To investigate whether topical application of KET peutic value for patients with allodynia or hyperal- is able to change mechanical threshold in CRPS I, gesia. we determined the patient’s touch and pain thresh- olds using von Frey filaments before and after KET Case Reports application. The touch threshold was defined as the pressure (measured in millinewtons) necessary to Patient 1 evoke sensation of touch. The pain threshold was A 36-year-old man injured his right hand by measured as the pressure (mN) required to evoke carelessly using an iron-compressing machine. noxious sensation. We observed that hyperalgesia Later he developed a spontaneous, unendurable and allodynia of the affected hand improved 20 pain of the injured hand. The pain was accompa- minutes after topical application of 0.5% KET. nied by severe swelling. Although radiologic exam- Thereafter, touch threshold increased from 1.47 ination did not reveal any abnormalities, hypesthe- mN to 4.31 mN, and pain threshold increased from sia and dysesthesia of thumb, index, and long 29.4 mN to 49.0 mN, respectively. These results fingers were found during clinical examination. showed that peripherally administered 0.5% KET Five days after the injury, a traumatic nerve lesion attenuates not only nociceptive but also nonnox- was suspected, and a surgical carpal tunnel release ious touch and pressure signals. was performed. One week after surgery, the hypesthesia of the fingers improved, but the allodynia, Patient 2 spontaneous burning, and motion pain remained A 48-year-old man suffered whiplash injury in a unchanged. Eventually, the patient developed in- traffic accident in 1994. Eventually, he developed creased sweating of the affected hand and was re- swelling of the right hand and complained of nau- ferred to our clinic for treatment. sea, vomiting, and headache. Magnetic resonance We performed a diagnostic examination includ- imaging analysis of cervical spine showed only a ing phentolamine and tourniquet tests, thermo- mild disc bulging. Appropriate medications and gram and bone scintigram, and suggested CRPS I as physical therapy were prescribed. Treatment con- a diagnosis. Oral medications, including alpha- tinued for 2 years. Despite the treatment, the pa- blockers, NSAIDs, and intravenous regional sympa- tient developed spontaneous burning pain and in- thetic blocks, were initiated as a treatment. As a creased and nearly continuous sweating of the result, the pain score improved (visual analog scale entire upper right limb. At this time, radiologic [VAS]: 8 3 5.6). The increased sweating also sub- examination suggested CRPS I, and the patient was sided. However, the remaining allodynia prevented treated with stellate ganglion and continuous epi- the patient from returning to work. To cope with dural blocks and transcutaneous electrical stimula- allodynia, we applied hydrophilic ointment (100 g) tion. The treatment lasted for an additional 2 years. containing 0.25% KET. Other components of the As a result, swelling of the affected arm has partially ointment were white petrolatum (25 g), cetanol improved, although pain has not subdued. The pa- (20 g), propylene glycol (12 g), polyoxyethylene 60 tient was then referred to our hospital where he hydrogenated castor oil (4 g), glycerol monostear- received alpha-blockers and amitriptyline hydro- ate (1 g), methyl paraoxybenzoate (0.1 g), propyl chloride. An intravenous regional sympathetic paraoxybenzoate (0.1 g), and distilled water. It was block was performed. This treatment normalized applied to the affected hand 3 times a day. No sweating and improved symptoms of spontaneous apparent changes of the symptoms were observed burning pain. Paresthesia and allodynia, however, immediately after application. Three days later, remained unchanged. To treat remaining symp- however, the allodynia decreased. We then in- toms, 0.8% KET ointment was applied 3 times a creased the concentration of KET to 0.5% and ob- day. One week later, the color of affected arm has served a further decrease in the allodynia and hy- significantly improved. The allodynia and paresthe- peralgesia as rapidly as 20 to 30 minutes after sia were attenuated as well (VAS: 8.5 3 4.8). starting the application. We continued applications using 0.5% KET and applying the ointment 3 times Other Cases a day. Two days later, the swelling, increased sweating, and the color of the hand improved. The VAS Having observed improvements of CRPS symp- improved to 2.1 2 weeks later; improvement of the toms after using KET ointment on 2 patients de- 526 Regional Anesthesia and Pain Medicine Vol. 27 No. 5 September–October 2002 scribed previously, we used it on another 3 patients with CRPS I and on 2 patients with CRPS II (Table 1). Relief of pain, at least partial relief, was reported by 2 CRPS I patients 1 to 2 weeks after KET administration began. No pain relief was achieved in CRPS II patients. 4.5 Not efficient 7.2 Not efficient 4.8 Partial, efficient 5.6 Not efficient 1.6 Efficient 1.8 Efficient 2.1 Efficient 3 3 3 3 3 3 3

Discussion and After Treatment Results VAS Before Our ﬁndings suggest that topical application of an ointment containing KET within the range of concentration from 0.25% to 1.5% is an additional KET 1.5% 4.8 1.5% 6.8 0.8% 8.5 1.0% 5.3 1.5% 4.5 approach to attenuate allodynia in CRPS I patients. 0.5% 5.6

Although the speciﬁc mechanism of KET action in Concentration our study remains unclear, we suggest that local anesthetic effects of KET are relevant; it was reported that intracutaneous injections of 0.1% KET cause hypesthesia to noxious and nonnoxious me- of KET Medications Used Before, 17 Administration During, and After Carbamazepine, amitriptyline Carbamazepine, amitriptyline Alpha-blockers, NSAIDs, amitriptyline NSAIDs and amitriptyline Alpha-blocker 1.5% 4.8 NSAIDs and amitriptyline chanical stimulations. Interestingly, the analgesic Alpha-blocker, NSAIDs, etc. effects of KET ointment were noticed at the concentration of KET as low as 0.25% (ketamine hy- Bone drochloride used in this study contained equal Atrophy amounts of dextro [R] and levo [L] isomers). It is ϪϪ ϪϪ Ϫϩϩ ϪϪ Ϫϩ ϪϪ ϩϩ / / / / / / likely that if it were injected in the affected area /

directly, similar analgesic effects might have al- Allodynia lowed an even lower concentration to be effective. Hyperalgesia/ This is important because the lowest concentration Pain of KET reported to date that produces local analge- Motion sic effects is 0.3%.18 Therefore, some other mechanism(s) may be at work as well. ϩϩϩ ϪϪϩ ϩϩϩ ϩϩϩ ϩϩϩ ϩϩϩ ϩϩϩ

Another possible explanation of the efﬁciency of Pain

KET ointment is its action on NMDA receptors. Spontaneous Animal studies identiﬁed several glutamate receptors, such as NMDA, amino-3-hydroxy-5-methyl- CRPS Cases Treated With Ketamine Lotion 4-isoxazolepropionic acid and kainate with action on unmyelinated, myelinated, and postganglionic

sympathetic axons. It was suggested that these pe- Table 1. Findings of the ripherally distributed receptors play a role in the Affected Lesion transmission of sensory signals to the central ner- Appearance and Physical Contracture increased sweating Contracture and skin atrophy Contracture vous system.20,21 These findings are supported by Contracture, swelling, and increased sweating the clinical report that intraplantar injections of glutamate or glutamate receptor agonists result in nociceptive behaviors similar to mechanical hyper- the finger finger fracture algesia and allodynia. These nociceptive behaviors the palm can be attenuated by peripheral administration of NMDA and non-NMDA receptor antagonists.15 In Disease Injury

addition, peripheral administration of MK-801, a Duration of noncompetitive antagonist of NMDA receptors, produces local anesthetic-like effects on the periphery.22 In another human study, very low concen- trations of peripherally administrated KET inhibited burn and injury-induced secondary hyperalgesia, suggesting that peripheral NMDA receptors are likely involved in peripheral sensory signaling.20 I CRPS I 36 (M) 4 mo Contusion of II CRPS I 38 (F) 8 mo Carpal bone V CRPS I 48 (M) 5 yr Whiplash Contracture, swelling, and III CRPS I 60 (M) 8 mo Contusion of VI CRPS II 29 (F) 10 mo Finger bite Skin atrophy IV CRPS I 34 (F) 3 yr Wrist sprain Swelling Abbreviations: M, male; F, female. VII CRPS II 56 (M) 15 yr Amputation of

Importantly, we observed a difference in the ef- Case Type Age (Sex) fectiveness of KET in CRPS I and CRPS II patients. The Effect of Ketamine Ointment • Ushida et al. 527

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