Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain

Ching-Yue Yang Chih-Shung Wong MDPhD Jang-Yang Chang ~ Shung-Tai Ho Purpose: Ketamine has been administered epidurally and intrathecally for operative and post-operative pain control. Animal studies showed potentiation of analgesia induced by ketamine and morphine. We hypothesized that intrathecal ketamine would potentiate the effects of intrathecal morphine in the treatment of cancer pain. Methods: A double blind, cross over study was designed to evaluate the effect of ketamine on spinal morphine analgesia in terminal cancer pain patients. A two-phase protocol was used; phase M, intrathecal morphine alone twice daily; phase M+K, co-administration of ketamine (1.0 mg) with morphine intrathecally twice daily. The dose of morphine was titrated upwards until acceptable pain relief was achieved, defined by numeric rating scales (0-10) _<3,and the rescue dose of morphine was less than 5 mg after each intrathecal administration for two days. The dose of intrathecal morphine was defined as the effective dose. Results: The effective dose of intrathecal morphine in phase M of 0.38 +- 0.04 mg .day-j was higher than that in phase M+K - (0.17 +_0.02 rag.day-I) (P < 0.05). The average pain scales were 7.95 +_0.25 before intrathecal drug administration. Pain scales were decreased to 2.2  0.17 (P < 0.05) in phase M and 1.95  0.20 (P < 0.05) in phase M+K after the effective dose of morphine had been reached. No serious side effects were observed in this study. Conclusion: The present study demonstrates that ketamine enhances the analgesic effect of morphine, thus reducing the dose of intrathecal morphine. Objectif." La kdtamine a dtd administrde par l'approche dpidutale et sous-arachno'tdienne pour contr~ler la douleur per- et postopdratoire. Des dtudes chez l'animal ont rdvdld que l'analgdsie ~tait potentialis#e lorsque la kdtamine dtait associde it la morphine. Nous avons vdrifid si la ketamine sousarachno'idienne potentialisait la morphine sous-arachno~dienne dans le traitement de la douleur du cancer. Mdthodes: Cette dtude en double aveugle entrecrois#e visait it ~valuer l'effet de la k~tamine sur la morphine sous-arachno'tdienne administrde it des cancdreux en phase terminale. Un protocole en deux phases a dt# dlabord pour la voie sousarachno'tdienne: phase M, morphine seule deux fois par jour; phase M +K, association de k~tamine (1,0 rag) avec morphine deux fois par jour. La dose de morphine a dtd augmentde jusqu'it ce qu'un niveau acceptable de soulagement soit atteint, ddfini sur une dchelle numdrique (0-10) <_3,et la dose de sauvetage de morphine a #td infdrieure it 5 mg apr~s chaque administration sous-arachno'Mienne pour deux jours. La dose de morphine dtait ddfinie comme la dose efficace. Rdsultats: En phase M, la dose efficace de morphine sousarachno~dienne de 0,38  0,04 mg .j-i a dt~ plus dlevde qu 'en phase M+K (0,17 +_0,02 mg .j-i (p < 0,05). Les ~chelles d'~valuation de la douleur moyenne dtaient de 7,95 +_0,25 avant l'injection sous-arachno'Mienne. Ces dchelles ont baissd it 2,2  0,17 (P < 0,05) en phase M e t it 1,95  0,20 (P < 0,05) en phase M+K une fois la dose efficace de morphine atteinte, ll n 'y a pas eu d'effets secondaires s~rieux. Conclusion: La prdsente dtude montre que la kdtamine augmente l'effet analgdsique de la morphine et rdduit ainsi la dose de morphine sous-arachno~dienne. 1 2 3 4 5 6 7 8 9 10 TABLEI. Profileof patients Location of pain Spinal ketamine has been used for postoperative pain control and produces spinal anaesthesia after intrathecal administration. ~-3 Animal experiments showed that intrathecal administration of ketamine, with benzethonium chloride as preservative, was not associated with macroscopic abnormalities in the spinal cord.4,5 Intrathecal morphine has been used for cancer pain control, especially in patients who experience inadequate analgesia, intolerable side effects or who have an excellent response to intrathecal administration.6 However, it is associated with many side effects, such as pruritus, nausea, vomiting, urinary retention, respiratory depression and tolerance.7 Animal studies have shown potentiation of analgesia by a combination of ketamine and morphine,8'9 suggesting that ketamine involves opioid interaction. This study, in patients with terminal cancer pain, was designed to determine whether intrathecal ketamine potentiated in-trathecal morphine, and decreased its side effects. M e t h o d s Twenty hospitalized patients, 10 men and 10 women, aged 22 to 69 yr were selected from patients referred to the Tri-service General Hospital, National Defense Medical Center from October 1993 to July 1995. The primary diagnosis included metastatic cervical cancer; lung cancer; hepatoma; colon cancer; pancreatic cancer and stomach cancer (Table I). The study was approved by the Ethics Committee o f Health of the hospital, its nature and purpose were described and written informed consent was obtained from each participant. All patients used opioid analgesics for pain control before the study and the pain was o f variable severity with pre-study analgesics. They all agreed to be implanted with an intrathecal Port-A-Cath (Pharmacia Deltec Inc. St Paul, MN 55112 U.S.A.), a catheter for intrathecal drug injection, ~~to control cancer pain. After implantation, the study was divided into two phases. In phase M (morphine), intrathecal morphine was given alone twice daily; and in phase M+K (morphine plus ketamine), ketamine 1.0 mg with benzethonium chloride as preservative was combined with morphine intrathecally twice daily. Intrathecal treatment began after random assignment to either phase M or phase M+K, with concomitant medications such as tranquilizers, bronchodilators or laxatives continued as previously. A double dummy technique was used, so that the patient, investigator and nurse were unaware o f the dose o f morphine and ketamine. The intrathecal dose o f morphine started at 0.05 mg and was .increased in daily incremehts not exceeding the previous daily dose until acceptable analgesia was obtained (see below). The injected drug was flushed with 2 ml normal saline to ensure entrance into the intrathecal space (volume of reservoir and catheter of Port-A-Cath <0.7 ml). A rescue dose o f 5 mg morphine im was administered as needed for pain. Doses of intrathecal morphine were increased until acceptable analgesia or the effective dose was achieved, i.e., rescue doses of morphine of <5 mg after each intrathecal administration and pain scale was <3. After achieving and maintaining acceptable analgesia for 48 hr in the first phase of the study, patients were randomly crossed over to the alternate phase, again starting with intrathecal morphine titration. ,There was no washout period between two phases. Self-assessment of pain, life interference and sleep deprivation were evaluated on a 0 - 1 0 numeric rating scale. Patients were asked to rate their p a i n f r o m 0 (no pain at all) to 10 (the worst pain ima (...truncated)