Anesth Analg 2004;98:557-558
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000077713.21575.07
LETTERS TO THE EDITOR
Local Anesthetic Switching for Intrathecal Tachyphylaxis in Cancer Patients with Pain
Chih-Ping Yang, MD,
Chun-Chang Yeh, MD,
Chih-Shung Wong, MD PhD, and
Ching-Tang Wu, MD
Division of Anesthesiology, Armed Forces Taoyuan General Hospital, Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
To the Editor:
Mercadante et al. (1) reported four cases that responded poorly to intrathecal morphine and bupivacaine for pain relief, and as a result they switched to morphine and lidocaine, which improved the analgesia. They concluded that this phenomenon was due to tachyphylaxis of local anesthetics. We agree partly their opinion.
Opioids may also activate the pain facilitatory system via activation of the N-methyl-D-aspartate (NMDA) receptors, which may produce hyperalgesia/allodynia (2–7) Indeed, NMDA antagonists have been demonstrated particularly effective in reducing persistent pain associated with central sensitization (8) Moreover, the central nervous system can synthesize and release neuropeptides that act via endogenous and exogenous opioid receptors to attenuate analgesic effects (9) As more opioids are given, more antiopioid peptides are released, thereby leading to attenuation of the analgesic effect of opioids.
We have managed a case of complex regional pain syndrome type 1 of left foot pain relief for 2 yr. Initially, lumbar epidural pain control with morphine and bupivacaine was prescribed. The patient obtained adequate pain relief (VAS 9 to 5) and resumed walking with a dose of 8 mg of morphine and 80 mg of bupivacaine daily. After 8 wk, a progressive decrease of analgesic effect (VAS 5 to 7) was found; thereafter, bupivacaine was substituted with lidocaine 320 mg daily. This change provided better pain relief (VAS 7 to 5) and allowed the patient to walk again for about 6 wk. Alternatively, we switched lidocaine and bupivacaine for 1 yr, if the analgesic effect was reduced. However, tolerance to morphine (8 mg to 12 mg/day) and persistent hyperalgesia/allodynia (VAS 9) were noted gradually. Subsequently, ketamine 80 mg/day was added for 2 mo. The VAS pain score was reduced from 5 to 3 and hyperalgesia/allodynia was reduced to VAS 5. Naloxone 10 µg/day was also prescribed for another 2 mo. Morphine was gradually reduced to 10 mg/day, and the hyperalgesia/allodynia was reduced to VAS 3.
In conclusion, besides tachyphylaxis of local anesthetics, the opioid-induced hyperalgesia and tolerance must be considered. From a clinical viewpoint, an appropriate medication for preventing both opioid-induced hyperalgesia and tolerance would be the concomitant use of opioid agonists (morphine), NMDA receptor antagonists (ketamine), and antiopioid antagonists (naloxone) (9).
References
- Mercadante S, Villari P, Ferrera P, Arcuri E. Local anesthetic switching for intrathecal tachyphylaxis in cancer patients with pain. Anesth Analg 2003; 97: 187–9.[Abstract/Free Full Text]
- Arner S, Rawal N, Gustafsson LL. Clinical experience of long-term treatment with epidural and intrathecal opioids: A nationwide survey. Acta Anaesthesiol Scand 1988; 32: 253–9.[Web of Science][Medline]
- De Conno F, Caraceni A, Martini C, et al. Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine. Pain 1991; 47: 337–9.[Web of Science][Medline]
- Célèrier E, Laulin J, Larcher A, et al. Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Res 1999; 847: 18–25.[Web of Science][Medline]
- Célèrier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology 2000; 92: 465–72.[Web of Science][Medline]
- Dunbar SA, Pulai IJ. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998; 284: 678–86.[Abstract/Free Full Text]
- Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993; 52: 259–85.[Web of Science][Medline]
- Oatway M, Reid A, Sawynok J. Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat. Anesth Analg 2003; 97: 168–73.[Abstract/Free Full Text]
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Response
S. Mercadante, MD,
P. Villari, MD,
P. Ferrera, MD, and
E. Arcuri, MD
Anesthesia and Intensive Care Unit and Pain Relief and Palliative Care Unit, La Maddalena, Cancer Center, Palermo, Italy
In Response:
Yang et al. raise a relevant topic in pain management, that is the complex phenomenon of tolerance and hyperalgesia associated with opioid use, either systematically or spinally administered. Clinical and experimental studies suggest that opioids, intended to abolish pain, can unexpectedly produce abnormally heightened pain sensations, which are characterized by a lowering of the pain threshold (hyperalgesia), and pain elicited by normally innocuous stimulation (allodynia) (1). Such abnormal sensations have been described as being quantitatively different from normal pain sensation and differentially localized from the site of the original pain complaint. These conditions are difficult to identify and controversies exist about the real occurrence of this phenomenon in clinical setting.
We reported patients who had several elements suggestive for such a syndrome, in which increasing pain was pursued by escalating opioid doses, which resulted in a worsening of the clinical picture. Of interest, interruption of this vicious circle by administering spinal local anesthetics was effective in minimizing hyperalgesia in two advanced cancer patients (2). Although much experimental data exist to explain these clinical changes of opioid response, no data exist on how, when, and why this occurs. This should be the challenging future question to resolve in appropriate cancer pain models.
While we do not exclude that this mechanism is operating in clinical practice, the cases presented in our paper focused on local anesthetic activity (3), considering that the improvement in analgesia was obtained without changes in intrathecal opioid doses. On the other hand, experimental work has also underlined the antihyperalgesic effect of local anesthetics, particularly lidocaine, resembling in some way ketamine at the level of the spinal cord (4).
No doubt that the use of epidural ketamine proposed by Yang et al. could be helpful in the context of opioid-induced hyperalgesia, according to the theory of a common pathway occurring for opioid-induced tolerance and hyperalgesia, associated with a state of hyperexcitation implicating NMDA-receptor activation (1). However, similar effects could potentially be obtained with systemic ketamine. The use of naloxone is even more controversial and debated in literature, despite encouraging reports and experimental data (5,6) and should be carefully assessed. More studies are needed to assess the most appropriate methods to reduce the phenomenon of hyperalgesia occurring with increasing doses of opioids.
References
- Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 2002; 100: 213–7.[Web of Science][Medline]
- Mercadante S. Hyperalgesia: an emerging iatrogenic syndrome. J Pain Symptom Manage 2003; 26: 769–75.[Web of Science][Medline]
- Mercadante S, Villari P, Ferrera P, Arcuri E. Local anesthetic switching for intrathecal tachyphylaxis in cancer patients with pain. Anesth Analg 2003; 97: 187–9.
- Koppert W, Ostermeir N, Sittl R, et al. Low-dose-lidocaine reduces secondary hyperalgesia by a central mode of action. Pain 2000; 85: 217–24.[Web of Science][Medline]
- Crain SM, Shen KF, Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment. Proc Natl Acad Sci U S A 1995; 92: 10540–4.[Abstract/Free Full Text]
- Mercadante S, Villari P, Ferrara P. Naloxone in treating central adverse effects during opioid titration for cancer pain. J Pain Symptom Manage 2003; 26: 691–3.[Web of Science][Medline]
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