Case Reports  |   May 2002
Ketamine Combined with Morphine for the Management of Pain in an Opioid Addict
Author Affiliations & Notes
  • Guy Haller, M.D.
  • Jean-Luc Waeber, M.D.
  • Nicoline Kooger Infante, M.D.
  • François Clergue, M.D.
  • *Staff Anesthesiologist, †Chief Anesthesiologist, ‡Professor and Chairman.
  • Received from the Division of Anesthesiology, Department of Anesthesiology, Pharmacology, Intensive Care of Surgery (APSIC), University Hospitals Geneva, Geneva, Switzerland.
Article Information
Case Reports
Case Reports   |   May 2002
Ketamine Combined with Morphine for the Management of Pain in an Opioid Addict
Anesthesiology 5 2002, Vol.96, 1265-1266. doi:
Anesthesiology 5 2002, Vol.96, 1265-1266. doi:
WITH an estimated prevalence of 3–8 problem drug users (mainly heroin) per 1,000 inhabitants in the European Union, 1 it is not unusual to see patients with opioid addictions undergoing elective or emergency surgery. They can sometimes be difficult to treat in the postoperative period because they may have increased pain scores and opioid requirements. 2 Recently, some authors suggested that morphine-induced analgesia could be enhanced by adding low-dose ketamine. 3 We report the successful treatment of an opioid addict patient with this drug combination.
Case Report
A 26-yr-old woman was admitted for trauma after a suicide attempt. Fractures of several lumbar vertebral bodies, without spinal injury, were diagnosed. The patient had no history of surgery for chronic pain but was known to have chronic substance abuse (heroin and methadone). Spinal fusion at T12–L1 was performed during general anesthesia. As the patient recovered, soon after the operation, she reported intense low-back pain evaluated as 10 out of 10 on a visual analog scale (VAS). During the first 7 hours after the procedure, she received a cumulative intravenous dose of 4 g proparacetamol, 0.45 mg clonidine, and, by a patient-controlled analgesia device, 290 mg morphine. She became sedated, with only partial pain relief (VAS, 5 out of 10). During the next 24 h, despite proparacetamol (8 g), clonidine (0.45 mg), and her usual methadone substitution (40 mg), morphine consumption increased to 430 mg/day without any improvement in pain relief (VAS, 5–7 out of 10).
No respiratory depression was observed, but the patient became slightly confused and opened her eyes only to tactile stimulation. A continuous low-dose ketamine regimen was then initiated according to a previously published protocol. 4 Ketamine infusion was started at 10 μg · kg−1· min −1and then was progressively reduced by steps of 2.5 μg, over a period of 45 min, to a final dose of 2.5 μg · kg−1· min−1. Improvement in pain relief became evident in the hour after the beginning of the infusion (VAS, 2 out of 10), and morphine consumption (patient-controlled analgesia) decreased to 160 mg/day. There were no ketamine-related adverse effects (psychotomimetic effects or impairment in cognitive functioning), and the patient had oriented verbal response and movements to orders. The same ketamine–morphine regimen was used until the fifth postoperative day, with a daily morphine consumption (patient-controlled analgesia) between 120 and 160 mg. The VAS score remained between 2 and 4 out of 10 while the patient was at rest and moving in bed.
On the fifth postoperative day, as she started to move out of bed, she felt intractable pain (VAS, 7– 10 out of 10) and did not respond to the usual treatment. A computed tomography scan showed two misplaced screws at the T12–L1 level. They were removed on the same day. After this second operation, a continuous infusion of ketamine at 2.5 μg · kg−1· min−1was used for a period of 2 days, combined with oral morphine (on demand), 8 g proparacetamol, and 40 mg/day methadone substitution. The patient used 200 mg (equivalent to 66 mg intravenous morphine) the first 48 h and progressively reduced the dose to 150, 60, 50, and 20 mg, respectively. Morphine was then stopped and replaced by 200 mg tramadol and 4 g paracetamol. The VAS pain score remained at 3 out of 10 or below, and no neurologic sequelae were observed. Follow-up was performed by a psychiatrist and our drug addiction support unit, and the patient left the hospital with a substitution treatment of 40 mg/day methadone.
The combination of low-dose ketamine and morphine provides clinicians with an interesting tool to improve pain management in postoperative patients and to reduce opioid-related adverse effects. 5 Our observation illustrates the new potentialities offered by this combination for patients with increased opioid requirements, particularly patients addicted to heroin.
Ketamine interacts as an antagonist-agonist of the μ and κ opioid receptors and an agonist of the noradrenergic (α2) and 5-hydroxytryptamine receptors (antinociceptive brain stem and midbrain descending pathways). 6 Ketamine is also a noncompetitive antagonist of the N  -methyl-d-aspartate receptors. 7 Located in supraspinal and spinal structures, mainly within the substantia gelatinosa of the dorsal horn, N  -methyl-d-aspartate receptors are a part of the postsynaptic excitatory system (nociceptive neurone). Their activation after repeated C-fiber stimulation results in an important increase of activity of the nociceptive neurone, underlying many forms of central sensitization and hyperalgesia. 8 Repeated or even single opiate administration seems to be able to initiate or enhance the activation of N  -methyl-d-aspartate receptors in exactly the same way as repeated C-fiber stimulation. 9,10 This results in the reduced potency of the analgesic effects of opiates, defined as tolerance. This may explain the morphine-sparing effect of an N  -methyl-d-aspartate antagonist, such as ketamine, and its potential benefits in treating a number of painful conditions, such as acute postoperative pain. Ketamine does not only prevent the development of tolerance, but it can also reverse systematically induced morphine tolerance and restore morphine effectiveness. 11 This latter point is particularly interesting in opioid addict patients who differ from usual postoperative patients by their high preoperative tolerance to opiate analgesia and their potential risk for development of tolerance-associated hyperalgesia.
As pain relief increases, morphine requirements are reduced (from 430 mg to 160 mg in our case), as are the incidence of drug-related adverse side effects. Therefore, we recommend considering the use of low-dose ketamine associated with morphine in patients with a detrimental shift of the dose–response curve for morphine.
The authors thank Martin Tramer, M.D., D.Phil. (Chief Anesthesiologist, Department APSIC, University Hospitals Geneva, Geneva, Switzerland), for his advice.
European Monitoring Center for Drugs and Drug Addiction: Extended annual report on the state of the drugs problem in the European Union. Luxembourg, Office for Official Publications of the European Communities, 2000
Rapp SE, Ready LB, Nessly ML: Acute pain management in patients with prior opioid consumption: A case-controlled retrospective review. Pain 1995; 61: 195–201Rapp, SE Ready, LB Nessly, ML
Suzuki M, Tsueda K, Lansing PS, Tolan MM, Fuhrman TM, Ignacio CI, Sheppard RA: Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg 1999; 89: 98–103Suzuki, M Tsueda, K Lansing, PS Tolan, MM Fuhrman, TM Ignacio, CI Sheppard, RA
Adriaenssens G, Vermeyen KM, Hoffmann VLH, Mertens E, Adriaensen HF: Postoperative analgesia with i.v. patient-controlled morphine: Effect of adding ketamine. Br J Anaesth 1999; 83: 393–6Adriaenssens, G Vermeyen, KM Hoffmann, VLH Mertens, E Adriaensen, HF
Schmid RL, Sandler AN, Katz J: Use and efficacy of low dose ketamine in the management of acute postoperative pain. Pain 1999; 82: 111–25Schmid, RL Sandler, AN Katz, J
Hirota K, Lambert DG: Ketamine: Its mechanism(s) of action and unusual clinical use (editorial). Br J Anaesth 1996; 77: 441–4Hirota, K Lambert, DG
Rogawski MA: Therapeutic potential of excitatory amino acid antagonists: Channel blockers and 2,3-benzodiazepines. Trends Pharmacol Sci 1993; 14: 325–31Rogawski, MA
Dickenson AH: Spinal cord pharmacology of pain. Br J Anaesth 1995; 75: 193–200Dickenson, AH
Mao J, Price DD, Mayer DJ: Mechanisms of hyperalgesia and morphine tolerance: A current view of their possible interactions. Pain 1995; 62: 259–74Mao, J Price, DD Mayer, DJ
Larcher A, Laulin JP, Celerier E, Le Moal M, Simonet G: Acute tolerance associated with a single opiate administration: Involvement of N  -methyl-D  -aspartate-dependant pain facilitatory systems. Neuroscience 1998; 84: 583–9Larcher, A Laulin, JP Celerier, E Le Moal, M Simonet, G
Schimoyama N, Schimoyama M, Inturrisi CE, Elliott KJ: Ketamine attenuates and reverses morphine tolerance in rodents. A nesthesiology 1996; 85: 1357–66Schimoyama, N Schimoyama, M Inturrisi, CE Elliott, KJ