Effect of Intrathecal Dexmedetomidine on Spinal Morphine Analgesia in Patients with Refractory Cancer Pain

Introduction

Intraspinal administration of opioids was often used for better analgesia in patients with refractory cancer pain to reduce the opioid consumption and possible side effects.^1–4 However, intrathecal administration of morphine can still induce some worrisome side effects such as nausea, vomiting, and pruritus. Consequently, some drugs such as bupivacaine, clonidine, and ketamine have been used as adjuvants to reduce morphine consumption and provide potent analgesia. However, they were limited by their own side effects, primarily sensory and motor blockade as well as hemodynamic instability.^2–5

There is a high density of α₂-adrenoceptors in the superficial dorsal horn of the spinal cord. ⁶ Intrathecal and epidural administration of α₂-agonist clonidine have been demonstrated to provide analgesia by both presynaptic and postsynaptic mechanisms, ⁷ and α₂-adrenoceptor agonists were also reported to offer specific advantages in neuropathic pain. ⁸ Recent studies have shown that refractory cancer pain was often combined with neuropathic pain. ⁹ Therefore, we postulated that intrathecal administration of α₂-adrenoceptor agonist with morphine might provide improved effects in patients with refractory cancer pain than intrathecal morphine alone.

Dexmedetomitine, a selective α₂-adrenergic receptor agonist, exhibits sympatholytic, sedative, and analgesic effects. It is eight times more potent for the α₂-receptor than clonidine. ¹⁰ It is widely used in postoperative sedation and analgesia. In previous clinical studies, intravenous dexmedetomidine resulted in a significant opioid-sparing effect as well as a decrease in inhalational anesthetic requirements. ¹¹ Moreover, Gursoy et al. ¹² reported that systemic administration of α₂-adrenergic receptor agonists (dexmedetomidine or guanfacine) with morphine attenuated the expression of tolerance to the analgesic effect of morphine and enhanced the morphine analgesia in rats. However, administration of intrathecal dexmedetomidine with morphine has not yet been studied. Thus, the purpose of this study was to investigate the effect of intrathecal dexmedetomidine on spinal morphine analgesia in patients with refractory cancer pain.

Methods

Experimental procedure

The experimental procedure used is shown below (Fig. 1).

OPEN IN VIEWER

FIG. 1.

Experimental procedure.

Results

Patient demographics and baseline characteristics are summarized in Table 1. Two patients were lost to follow-up; a total of 24 patients were studied.

Pain intensity (numeric rating scale) and frequency (4-point verbal ordinal scale) on the day before intrathecal administration (baseline) were 6.9±1.2 and 2.4±0.5, respectively. During phase M, these decreased to 2.8±1.0 (p<0.05) and 0.8±0.4 (p<0.05), respectively, and to 2.4±1.0 (p<0.05) and 0.5±0.5 (p<0.05) during phase M+D, respectively (Fig. 2).

OPEN IN VIEWER

FIG. 2.

The mean values of pain intensity (visual analog scale [VAS]) and frequency (4-point verbal ordinal scale) on the day before intrathecal administration, during phase M and phase M+D. Value are mean±standard error of the mean [SEM], n=24. Phase M, intrathecal morphine only. Phase M+D, coadministered rated dexmedetomidine with morphine. *p<0.05 vs. before intrathecal administration.

Most of the patients had sleep deprivation before intrathecal administration, with scales (numeric rating scale) averaging 6.8±1.3, which were improved after intrathecal administration to 2.8±1.0 (p<0.05) and 2.4±0.6 (p<0.05) during phase M and phase M+D, respectively (Fig. 3).

OPEN IN VIEWER

FIG. 3.

Sleep deprivation on the day before intrathecal administration, during phase M and phase M+D. Value are mean±standard error of the mean (SEM), n=24. Phase M, intrathecal morphine only. Phase M+D, co-administrated dexmedetomidine with morphine. *p<0.05 vs. before intrathecal administration.

Daily morphine consumption and bolus dose injection times during phase M were 7.9±1.1 mg and 6.9±0.9 times, respectively. During phase M+D, they decreased to 5.3±0.8 mg (p<0.05) and 2.8±0.7 times (p<0.05), respectively (Fig. 4).

OPEN IN VIEWER

FIG. 4.

Daily morphine consumption and bolus dose injection times during phase M and phase M+D. Value are mean±standard error of the mean (SEM), n=24. Phase M, intrathecal morphine only. Phase M+D, coadministered dexmedetomidine with morphine. *p<0.05 vs. phase M.

Side effects were observed and are listed in Table 2. No serious side effects such as respiratory inhibiton, hypotension, or bradycardia were observed at any phase.

Discussion

Our results showed that patients with refractory cancer pain could be greatly relieved by intrathecal morphine alone or morphine plus dexmedetomidine. Furthermore, coadministration of dexmedetomidine with morphine could reduce the intrathecal morphine consumption.

There are two types of drug delivery system for intrathecal analgesia: external catheter and implantable infusion pumps. Because all cases were patients with advanced cancer expected to live 3 to 6 months, and due to economic considerations, an external catheter connected to a computerized ambulatory drug delivery (CADD) pump was used. This regimen was easy to operate and with relative low hospital cost but has risk of possible infection. In the present study, no case of infection was observed, which might be attributed to the small number of patients and short observation.

Several studies about epidural analgesia with intrathecal clonidine have been performed, but few studies on intrathecal dexmedetomidine administration were reported. A previous study indicated that systemic administration of dexmedetomidine with morphine attenuated the expression of tolerance to the analgesic effect of morphine and enhanced the morphine analgesia. ¹² Our results revealed that intrathecal administraion of dexmedetomidine with morphine reduced the morphine consumption in patients with refractory cancer pain. The daily intrathecal morphine consumption of phase M+D was significantly reduced than that of phase M. The synergistic effects of morphine and dexmedetomidine could explain this clear benefit on pain control.

Constipation was the most common side effect of opioids. Sixteen patients experienced constipation before intrathecal administration but intrathecal analgesia also produced some adverse reactions. First, nausea and vomiting were the most common adverse reactions, but could be tolerated by most patients after symptomatic treatment. Moreover, the reaction degree will be gradually attenuated with the time of intrathecal analgesia prolonged. Second, urination difficulty was also very common and often occurred in men but seldom in women. Urinary retention was the most troublesome complication and sometimes bladder catheterization was required. One patient developed transient hallucinations during phase M, because a large dose of morphine was required to relieve his pain. Hallucinations disappeared when the morphine dose was reduced during phase M+D. Also, three patients experienced somnolence during phase M and two additional patients experienced it during phase M+D. According to previous studies, dexmedetomidine could provide a unique quality of sedation similar to normal sleep. Under these circumstances, patients could be woken up by verbal stimulation and were able to communicate with the medical staff. The moderate sedation was a benefit for patients.

There were no serious side effects in this study such as life-threatening respiratory depression, hypotension, or bradycardia. The possible explanation might be attributed to the dose of intrathecal morphine was adjusted by titration and overdose was avoided. Although the incidence of some side effects was lower in the phase M+D than in phase M, the difference was not statistically significant, probably because of the small number of patients, brief trial period, and large dose of intrathecal morphine required. Future studies with larger sample size would be needed.

In conclusion, intrathecal administraion of dexmedetomidine with morphine reduced the morphine consumption in patients with refractory cancer pain. No serious side effects were observed. Thus, the concomitant use of intrathecal morphine and dexmedetomidine is an effective and safe method of refractory cancer pain control.