© U.S. Cancer Pain Relief Committee, 1999 0885-3924/99/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(99)00018-4

Vol. 18 No. 1 July 1999 Journal of Pain and Symptom Management 61

Original Article

Analgesic Effect of Oral Ketamine in Chronic Neuropathic Pain of Spinal Origin: A Case Report

Kim Fisher, PhD and Neil A. Hagen, MD, FRCPC

Clinical Neurosciences (K.F., N.A.H.) and Department of Oncology (N.A.H.), University of Calgary, Calgary, Canada, and Department of Medicine (N.A.H.), Tom Baker Cancer Center, Calgary, Canada

Abstract

Ketamine is an injectable anesthetic induction agent that has been reported to have analgesic activity in pain from a variety of mechanisms, but predominantly in neuralgic and dysesthetic neuropathic pain. In this case report we illustrate the effectiveness of ketamine in a patient with neuropathic pain resulting from cauda equina trauma. Among the issues addressed are the role of pretreatment with haloperidol to prevent ketamine-induced psychomimetic effects, the potential for fewer side effects and a need for lower doses when ketamine is administered orally, and the need for further study regarding appropriate monitoring parameters during the titration phase. Oral ketamine can be effective in treatment refractory chronic neuropathic pain of spinal origin.

J Pain Symptom Manage 1999;18:61–66

. © U.S. Cancer Pain Relief Committee, 1999.

Key Words

Ketamine, N-methyl-

D

-aspartate receptor, pain management, neuropathic pain,

oral administration

Introduction

Although ketamine is widely used as an anes-thetic induction agent, individual case reportsand subsequent controlled studies have pro-vided convincing evidence that treatment withsubanesthetic doses of this compound relieveschronic pain in some patients. Specifically, theadministration of ketamine has been shown toreduce central pain,

1–3

painful peripheral neu-ropathy,

4–7

postherpetic neuralgia,

8–11

orofacialpain,

12

fibromyalgia pain,

7,13,14

glossopharyngealneuralgia,

15

stump or phantom limb pain,

16–19

and cancer pain from a variety of mecha-nisms.

20–23

Unfortunately, the high prevalence of sideeffects has limited the widespread use of ket-amine. Following intramuscular,

12,24

intraven-tricular,

1,5,13,14,19,24–27

or subcutaneous

9

adminis-tration, ketamine can produce severe sideeffects, including sedation, dizziness, and psy-chomimetic effects including feelings of unre-ality, blurred vision, changes in hearing, andhallucinations. There may be fewer seriousside effects if the drug is administered intrathe-cally by a spinal catheter.

23

Haloperidol, mida-zolam, and other agents have been used to pre-vent or reduce psychomimetic effects associatedwith ketamine administration.

12,22,28

Relatively few published reports have exam-ined the analgesic and side effect profiles oforally administered ketamine. Single case re-

Address reprint requests to:

Neil A. Hagen, MD, FRCPC,1331 29th Street N.W., Calgary, Alberta, CanadaT2N 4N2.

Accepted for publication: September 21, 1998.

62 Fisher and Hagen Vol. 18 No. 1 July 1999

ports have suggested that oral ketamine im-proves glossopharyngeal

15

and postherpetic

10,11

neuralgia, stump or phantom limb pain,

17,18

fi-bromyalgia pain,

7

and painful peripheral neur-opathy.

6

Preliminary reports suggest that oralketamine may have a more favorable side effectprofile than parenteral ketamine, but directcomparative studies are lacking. We are un-aware of any reports of oral ketamine use inchronic neuropathic pain of spinal origin.

In this paper, we report the long-term effec-tiveness, safety, and tolerability of oral ket-amine in a patient with chronic spinal pain tohighlight the potential usefulness of oral ket-amine in this clinical setting and to foster dis-cussion regarding potential research directionsfor ketamine and related

N

-methyl-d-aspartate(NMDA) receptor blockers.

Case Report

In 1981, a 32-year-old man was in a motor ve-hicle accident which resulted in a metal rodbeing traumatically inserted into the bottom ofthe thecal sac. He was left with permanent bi-lateral motor and sensory impairment fromthe knees down and with impaired sexual andbladder function. He required a colostomy be-cause of trauma to the anal sphincter. Therewas mild, achy pain from the lower legs despitetheir numbness.

In 1989, he banged his right shin, withoutovert evidence of tissue damage. Since thatday, he experienced severe, persistent rightlower extremity neuropathic pain which he de-scribed as “a constant achiness.” On average,the patient rated it as “5/10” in severity, butthere was a circadian pattern to the pain, withworsening to an average of “8/10” in severityon most nights. Application of cold packs tothe right lower extremity provided some relief.

He also described spells in which light touchof either lower extremity below the knee wouldtrigger excruciating pain. These episodes wereinfrequent, occurring only a few times a year.However, each time he experienced these epi-sodes he would be admitted to hospital andtreated with parenteral opioids.

A third kind of pain was described as briefepisodes of “jabbing pain,” which would usu-ally occur every day. Occurring while walkingor spontaneously at rest, he would suddenlyhave an episode of excruciating pain in the

right lower extremity. There was never any visi-ble jerking of the right leg with these jabbingspells of pain.

He had partial relief of his pains with slowrelease codeine 150 mg twice daily, diazepam7.5 mg daily, baclofen 80 mg daily, amitrip-tyline 75 mg daily, and occasional acetamin-ophen with codeine tablets. He failed sequen-tial trials of carbamazepine, gabapentin, higherdoses of diazepam, and several differentopioids.

On physical examination, he exhibited flac-cid weakness from the midlumbar nerve rootdistribution downward and moderate sensoryimpairment. A large midline scar was presentover the lumbar region from prior placementand removal of Harrington rods. There wereno abnormalities in sweating, skin color, orskin temperature, and there were no otherskin or nailbed changes.

The patient exhibited after-sensation to lighttouch, which was characterized by a persistentfeeling of being touched after the right lowerextremity was gently rubbed with cotton or theexaminer’s finger. On occasion, the sensationwould swell into a worsening of baseline achi-ness that would crescendo after about 10minutes.

Rotation from amitriptyline to higher dosesof desipramine with documented high thera-peutic blood levels was associated with worsen-ing of pain, with severe, single, brief episodesof lancinating neuralgic pain in the right lowerextremity. Clonazepam titrated upwards to clin-ical toxicity relieved the jabbing pain only par-tially. The desipramine and clonazepam weretapered and discontinued. Subsequently, hefailed a second trial of carbamazepine and atrial of valproic acid.

After written informed consent, the patientwas admitted to an intensive care unit and wasstarted on subcutaneous (s.c.) ketamine with asingle injection of 10 mg and a continuous in-fusion of 3 mg per hour. He was pretreatedwith haloperidol 0.5 mg every 4 hours bymouth. Because the pain persisted, he was ad-ministered another bolus dose of 10 mg andthe dose was titrated over the next 30 hours up-wards to 4 mg and subsequently 5 mg per hour.He promptly obtained relief of all pains. Onlyon one occasion did he experience a brief epi-sode of a “floating, dreamy sensation,” whichwas associated with a bolus of s.c. ketamine.

Vol. 18 No. 1 July 1999 Ketamine in Treatment of Chronic Neuropathic Pain 63

Subcutaneous sites lasted about 1 day andneeded to be changed owing to mild erythemaand pain.

After 1 day of stable analgesia at a dose of 5mg per hour s.c., he was switched to oral ket-amine at a rate of 10 mg every 8 hours. Thedose was titrated upwards over the next 3 daysand after 1 week of hospitalization, he was dis-charged on a schedule of 25 mg of ketamine bymouth three times daily and haloperidol 0.5mg by mouth twice daily.

Several weeks following the commencementof the oral ketamine treatment, the patient dis-continued the haloperidol pretreatment. Sub-sequently, he slowly tapered baclofen over a7-week period, and he then tapered and dis-continued the slow-release codeine. When lastseen 5 months following the commencementof oral ketamine treatment, the patient’s painwas effectively managed with 25 mg of ket-amine three times daily without use of anyother regularly scheduled analgesic; baselinepain was “3/10” in severity. Occasional flares ofnocturnal pain responded well to either oralcodeine (100 mg) or diazepam (5 mg). He re-ported no side effects associated with the oralketamine, and indicated he has never had sucha prolonged period of pain relief since the mo-tor vehicle accident more than 16 years earlier.Strikingly, episodes of light touch–evoked painof the right lower extremity have disappearedsince the institution of ketamine.

Discussion

Empirical observation has for many yearsguided clinicians regarding the use of adjuvantanalgesics. The discovery that tricyclic antide-pressants have analgesic activity for severe neu-ropathic pain was fortuitous

29

and led to ran-domized controlled trials attesting to their roleas multipurpose analgesics.

30–34

More recentlyother medications have been observed to haveanalgesic activity, including many antiseizuremedications, heart rhythm disturbance drugs,antispasticity agents, and others. Often, suchobservations are followed by more careful study,usually including randomized controlled clini-cal trials.

Although preliminary observations regard-ing the analgesic activity of ketamine date back

several decades,

35,36

recent reports underscorethe potential utility of this anesthetic inductionagent in a variety of pain syndromes, predomi-nantly neuropathic pain syndromes.

1–12,15–19

The current report adds to these observationson the potential role of ketamine as an analge-sic agent and highlights several important is-sues, including its activity in neuropathic painof spinal origin, the role of pretreatment withhaloperidol to prevent psychomimetic side ef-fects, the potential for fewer side effects and aneed for lower dosages when administeredorally, and the need for further study regard-ing appropriate monitoring parameters in thetitration phase.

While ketamine has been reported to be ef-fective in a variety of pain states, including so-matic pain,

12–14

visceral pain,

23

and mixedpain,

23,28,37

greatest interest has focused on itseffectiveness in neuropathic pain,

1–5,8,9,12,15,19,22

including neuralgia, dysesthesia, and allodynia.These reports indicate that ketamine can be ef-fective for neuropathic pain arising from a vari-ety of locations throughout the peripheral andcentral nervous system. Relief of neuropathicpain following trauma to the cauda equina inthe patient who is the subject of this report sug-gests that pain of spinal origin can also re-spond to ketamine. Of particular interest is theobservation that oral ketamine treatment notonly reduced the patient’s spontaneous pain,but also abolished the light touch–evokedpain. This finding, which is consistent withother studies,

1,3,4,5,8,9,27,28

suggests that both ofthese types of pain symptoms are mediated bythe NMDA receptors. An appeal has beenmade towards physiologically based treatmentof neuropathic pain;

38

further study is neededto learn the value of light touch–evoked painas a potential predictor of response to NMDAreceptor antagonists.

Psychomimetic side effects are prominentwith ketamine use

1,4,5,8,9,12,14,27

which led us topretreat the patient with haloperidol to pre-vent these unwanted effects. Prior reports havesuggested that haloperidol

22

and midazolam

12,28

can be effective prophylactic agents. The mech-anisms mediating these psychomimetic effectsare likely complex; although the affinity of ket-amine for the phencyclidine (PCP) site on theNMDA receptor has been cited,

39

ketamine hasbeen reported to interact with a number of

64 Fisher and Hagen Vol. 18 No. 1 July 1999

different sites in the mammalian nervous sys-tem, including sodium

40

and calcium

41

chan-nels, as well as opioid,

39,42,43

acetylcholine,

39,44

and monoaminergic

45

receptors. Further re-search will be needed to delineate the opti-mum drug dosages and duration of prophy-laxis.

We were able to use lower doses of oral ket-amine than the parenteral ketamine requiredpreviously. This observation suggests that ket-amine may be a more potent analgesic whenadministered orally. In contradistinction, mostanalgesics, such as opioids, are found to be lesspotent when administered orally than parenter-ally. Compared to parenteral ketamine, oralketamine yields lower plasma ketamine levelsand higher norketamine levels.

46

The observa-tion that a peak in plasma norketamine con-centrations matches the analgesic effect in hu-man volunteers has led to the hypothesis thatnorketamine is analgesic.

46

The demonstrationthat (S)- and (R)-norketamine bind to the PCPsite in the rat spinal cord may support this hy-pothesis.

47

Until this issue is further characterized, clini-cians need to be aware that ketamine may bemore potent orally than parenterally. Further,the relative toxicities of ketamine comparedwith its metabolites such as norketamine arenot well delineated. It is possible that the fewerside effects observed when ketamine was ad-ministered orally were due to its lower dose orto a more favorable side effect profile of nor-ketamine compared with ketamine.

Because ketamine is an anesthetic inductionagent, we elected to admit the patient to the in-tensive care unit in order to titrate the medica-tion under careful monitoring. Further re-search is needed to delineate the risks ofinitiation of ketamine dosing. It is not clearthat patients need to be admitted to hospitalfor careful monitoring.

The overall analgesic strategy used by clini-cians in managing neuropathic pain usually in-volves that of sequential clinical trials of adju-vant analgesics, whereby a medication is startedat a low dose and the dose titrated upward sys-tematically until there is either relief of symp-toms, unwanted and unmanageable side effects,or a maximum dose is reached. While this ap-proach has been helpful to identify ketamineas having significant analgesic activity in some

patients, further research in the use of NMDAreceptor blockers, such as ketamine, is neededto guide clinicians to the appropriate selectionof patients, appropriate monitoring during ti-tration, use of medications to prevent neuro-psychiatric toxicities, and equianalgesic dosingof parenteral compared with oral routes of ad-ministration. Our report adds to earlier publi-cations attesting to the potential effectivenessof ketamine in treating refractory neuropathicpain and indicates that oral ketamine can behelpful in pain of spinal origin.

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