Journal of Pain and Symptom Management
Volume 17, Issue 5 , Pages 384-386, May 1999

Clinical Experience with Oral Ketamine

  • Mark C Enarson, BSc

      Affiliations

    • Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada
    • ,
  • Helen Hays, MD

      Affiliations

    • Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada
    • Corresponding Author InformationHelen Hays, MD, 604 College Plaza, Edmonton, Alberta, Canada T6G 2C8
    • ,
  • Mary Ann Woodroffe

      Affiliations

    • Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada
    • ,
  • Bscn

      Affiliations

    • Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada

Accepted 31 August 1998.

Article Outline

Abstract 

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist used recently for analgesia in patients with chronic pain. Twenty-one patients with chronic neuropathic pain were treated with oral ketamine starting at a divided dose of 100 mg/day and titrating upwards by 40 mg/day until efficacy was reached, or until side effects became limiting. A retrospective chart review was conducted to evaluate the analgesic efficacy and side effects of the treatment. Nine patients discontinued ketamine because of intolerable side effects, four patients experienced few or no side effects but had no discernible benefit, four others had equivocal responses. Four patients have continued oral ketamine for long periods. One patient has had no significant benefit or side effects but continues to use ketamine 500 mg/day and three people have used doses ranging from 100–240 mg day for over 1 year duration and have reported improvements in pain and decreased use of analgesics. The analgesic benefits of ketamine appeared to be most pronounced in, but not limited to, patients with pain histories of less than 5 years.

Keywords:  Oral ketamine, NMDA, analgesia, neuropathic pain

 

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Introduction 

Ketamine is a commercially available N-methyl-D-aspartate (NMDA) antagonist which binds noncompetitively to the phencyclidine (PCP) site of the NMDA receptor.1 Traditionally, ketamine has been utilized as a general, dissociative anesthetic, which is indicated for short diagnostic and surgical procedures.2 More recently, a number of studies have detailed the successful use of ketamine, over short defined periods and in subdissociative doses, as an analgesic in patients with chronic nonmalignant pain.3, 4, 5, 6, 7, 8

In this report, we describe a retrospective review of 21 patients with chronic pain who were treated with oral ketamine as an adjunct to ongoing therapy with individualized combinations of opioids, anticonvulsants, and antidepressants.

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Patients and Treatments 

The patients (13 women, 8 men) were 29–81 years old and had been diagnosed with a variety of central and peripheral chronic neuropathic pain syndromes. All patients had been unresponsive or poorly responsive to standard analgesic therapies, including opioids.

The starting dose of oral ketamine was 100 mg/day (40 mg/day in patients who were hypersensitive to medications) in divided doses. This was titrated every 2 days by 40 mg/day until efficacy was reached or side effects became limiting. Final doses were 40–500 mg/day, with a median dose of 220 mg/day.

Attrition was high during the initial dose escalation. Five patients discontinued ketamine within the first 10 days. Nine patients reported side effects as the reason for discontinuing ketamine, with psychomimetic symptoms (“elevator” effect, dissociative feelings) the most frequently experienced, followed by alertness disturbances (somnolence or insomnia) and sensory changes (taste changes, numbness, tingling, hot, cold). Seven patients clearly experienced benefit from ketamine, but four chose to discontinue it due to intolerable side effects.

Four patients experienced few or no side effects from ketamine, but had no clearly discernible benefits at maximum daily doses of 200–380 mg over a period of 55–243 days. Four other patients had equivocal responses and it was difficult to determine if ketamine was a significant benefit. One patient continues to take ketamine 500 mg/day, without side effects, but does not report a significant benefit.

Three patients, (1 man, age 59; 2 women, ages 35 and 52) have done very well on ketamine (total daily dose ranging from 100 mg to 240 mg) and continue to experience pronounced benefit after taking the medication for at least 1 year. There have been improvements in pain, reflected by lower pain scores and decreased use of breakthrough analgesics. Additionally, these patients have reported improvements in mood, energy, activity, and sleep.

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Discussion 

Our experience in treating 21 patients with chronic nonmalignant pain with oral ketamine demonstrates the difficulty of many patients in tolerating this medication. There is anecdotal evidence for analgesic efficacy of ketamine for certain patients in this population. Although the three patients who received the most benefit from ketamine all suffered myofascial syndromes, the sample size is too small to determine if this is a meaningful observation.

It has been previously noted that young patients with short pain histories (less than 5 years) tend to benefit more from the analgesic potential from ketamine.4, 9 Our data do not support the assertion that young patients benefit more; two of our patients who had benefit were over 50 years of age. However, in our group, patients who received benefit from ketamine had pain histories of less than 5 years. Several researchers reported conflicting data;6, 7, 8 these studies involved short-term infusions of ketamine. Long-term outcomes will be important in future studies to clarify this important aspect of patient selection for using ketamine.

A striking aspect of ketamine therapy is the frequency and intolerable nature of side effects for many patients. Nearly 30% of the 21 patients discontinued the medication within 2 weeks of treatment. Troublesome psychomimetic side effects may be attenuated by premedicating with benzodiazepine,10 and had these agents been used, symptoms may have been more tolerable. However, Backonja et al.3 found that side effects were still problematic in their small group of patients using an infusion of ketamine, despite premedication with midazolam or lorazepam.

The side effects recorded by our patients are similar to those reported elsewhere.4, 6, 7, 11 With regard to psychomimetic side effects, it can be challenging to compare the experiences of different patients due to the difficulty of describing such experiences. Further, polypharmacy and the complex nature of chronic pain make side effect attribution a confounded exercise.

It is impossible to rule out a placebo effect in outcomes of treatments which are prescribed in an unblinded manner and when possible benefits and side effects are fully explained, as they were to our patients. These people may have expectations regarding outcomes and these factors may influence symptom perception.12 In addition, reliability of data depends on the accuracy of patient reporting. When studying a population of chronic pain patients, the strong emotional and psychological elements of the pain state may affect reporting. There have been similar difficulties and weaknesses in other published reports detailing uncontrolled trials of ketamine. Nevertheless, there has been consistency between the observed outcomes during ketamine therapy and the known pharmacology of this drug.

Ketamine has been shown to have numerous actions, each of which may play a role in analgesia.10, 13, 14 Many authors have focused on the activity of ketamine as a noncompetitive NMDA receptor antagonist. Other actions also may be involved, however, such as mood alterations, which may be related to its structural homology to PCP. Ketamine is recognized as a substance of abuse, although this is rare. Such behavior was not evident in our patients.* Because the pain experience is multidimensional, with strong emotional components,15 elements such as mood, sleep quality, and energy levels should be taken into account when assessing the efficacy of ketamine for patients with pain.

Treatment of patients with chronic pain is difficult and time-intensive, and often many types of medications, including analgesics and adjuvant agents, are tried to relieve suffering.16, 17 The balance of the available evidence suggests that ketamine may be an addition to this drug arsenal for some patients. It will be important for future research to be directed at long-term use of ketamine. Well-controlled studies are needed to examine efficacy and safety of this medication, as well as to better define issues of optimal dosing and patient selection.

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Acknowledgements 

The authors gratefully acknowledge the input of Olga Szafran, Research Coordinator, Department of Family Medicine, and Dr. Andrew Cave, Assistant Professor, Department of Family Medicine, University of Alberta, in reviewing this document. We would also like to thank Ron Marcinkoski, Pharmacist/Owner at TLC Pharmacy, Edmonton, for his technical support in the preparation and supply of ketamine, and the MRC Burroughs Wellcome Fund Student Research Award, Faculty of Medicine, University of Alberta, for its support of Mark Enarson.

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References 

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  • * None of the patients described remain on ketamine. Side effects were extremely limiting and benefits were difficult to evaluate, but probably small.

PII: S0885-3924(99)00011-1

Journal of Pain and Symptom Management
Volume 17, Issue 5 , Pages 384-386, May 1999

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