Intrathecal Buprenorphine in the Treatment of Phantom Limb Pain

Abstract

Phantom limb pain is a chronic pain perceived in an absent part of the body. It can totally consume a patient's life. Suggested treatments for this complaint are many, but none have proved to have lasting efficacy. We have treated two patients suffering from phantom limb pain. Intrathecal buprenorphine provided not only immediate and long-lasting pain relief, but also increased the temperature of the lower part of the body. These cases are described and possible mechanisms for the analgesic and hyperthermic actions of intrathecal buprenorphine are discussed. Case Reports Case 1 A 67-yr-old man presented with phantom pain in the right leg. Seven years previously, he suffered a right dislocated hip-joint and an occlusion of the right femoral artery in a traffic accident. His leg was amputated surgically 2 days after the accident. He had experienced phantom limb sensation and pain in his right leg since the operation. He described the pain as piercing and cramping in nature. It had been poorly managed with analgesics. The pain was present all the time but worse at the end of the day. As it had recently begun to worsen, and was interfering with his sleep, the patient was referred to our hospital. The patient was instructed to score the pain on a 10-cm visual analog self-rating scale (VAS) (0 = no pain, 10 cm = worst pain imaginable), and thermograms (Thermo Tracer 6T66 Trademark; San-Ei, Tokyo, Japan) were taken to trace the temperatures of the bilateral lower limbs during treatment. Epidural block with 0.25% bupivacaine was attempted but resulted in only temporary effects. On the next day, we attempted intrathecal administration of buprenorphine. The VAS before the administration was 10.0 cm and the temperatures of the left intact thigh and the right stump area were 33.5 degrees C and 29.4 degrees C, respectively. After the VAS and thermogram were taken, the patient was placed in a lateral recumbent position. A lumbar puncture was performed with a 25-gauge needle at the L3-4 intervertebral space and 0.2 mg of buprenorphine in 3 mL of normal saline was injected once a free flow of cerebrospinal fluid was obtained. After the injection, the patient was returned to the supine position and allowed to rest quietly while the VAS and the thermogram were recorded. The patient described an immediate warm sensation in his lower extremities and immediate relief of pain in his phantom limb. The VAS decreased from 10.0 to 0 cm 10 min after the injection and all phantom sensation disappeared. The thermogram after the injection also showed remarkable changes. The temperature of the lower half of the body increased; the temperatures of the left intact thigh and the right stump area increased from 33.5 to 35.0 degrees C and from 29.4 to 32.4 degrees C, respectively, by 30 min after the injection. Mean arterial blood pressure before the injection and 10 and 30 min after the injection was 102, 99, and 117 mm Hg, respectively, and heart rate was 80, 77, and 79 bpm, respectively. On the next day, although the phantom sensation reappeared, the pain was considerably less; the increased temperature of the lower extremity also continued for 3 days Figure 1. Thereafter, the phantom limb pain gradually returned and a second administration was scheduled 4 days after the first injection. The intrathecal administration was performed in the same manner as described for the first injection. The patient again described immediate and total pain relief, and the temperature of the stump area increased from 32.0 to 35.1 degrees C. This effectiveness continued for 5 days.Figure 1: Changes in visual analog scale (VAS) and temperature after intrathecal buprenorphine in the two patients. Temperatures shown were recorded at the stump areas. Squares and circles indicate VAS and temperature, respectively.The injection was performed a total of five times. The VAS scores were 0-2.0 cm during the successive intrathecal buprenorphine. Thereafter, the treatment was altered to buprenorphine suppositories used once daily, which the patient said was sufficient to relieve the pain. He was discharged with a supply of the suppositories, and reported excellent pain relief with the buprenorphine when he visited the outpatient clinic of our hospital 3 mo later. The VAS score was 2.4 cm. Case 2 A 65-yr-old woman was involved in a traffic accident, sustaining left lower limb injury. The wound became infected and she subsequently had an amputation above the left knee. After the operation, she described phantom limb pain and stump pain, which gradually increased. Five years later, the pain abruptly worsened after the patient had a bout with the flu and she was referred to our department for consultation. She was hospitalized and given continuous lumbar epidural administration of 0.25% bupivacaine. This provided good pain relief during administration, but she described resurgence of the phantom limb pain and stump pain as soon as administration was stopped. Intrathecal administration of buprenorphine was scheduled. The patient scored the pain and the temperature was analyzed as in Case 1. The VAS before the administration was 8.5 cm and the temperatures of the right intact thigh and the left stump area were 32.6 and 31.5 degrees C, respectively. The intrathecal administration of buprenorphine (0.1 mg) was performed in the same manner as described in Case 1. After the injection, the patient described an immediate warm sensation in her lower extremities and immediate pain relief in her phantom limb and the stump areas. The VAS decreased from 8.5 to 0 cm and the temperature of the stump area increased from 31.5 to 33.8 degrees C 30 min after the injection. This effectiveness continued for 4 days Figure 1. This treatment was performed a total of four times; thereafter, the patient was given buprenorphine suppositories and instructed to insert them at a regular hour at which she was comfortable. The pain is now well controlled using the buprenorphine suppositories. Discussion These case reports demonstrate that intrathecal administration of buprenorphine in patients with postamputation phantom limb pain produced complete and long-lasting relief of pain, abolished all or nearly all phantom sensation, and increased the temperature of the lower part of body. These effects lasted over 3 days. Buprenorphine is a semisynthetic, highly lipophilic opioid derived from thebaine. It has a complex profile from antinociception tests of mu opioid receptor partial agonism and putative kappa antagonism [1,2], and has a systemic potency of 20-70 times that of morphine [3,4]. Nonionized drugs such as buprenorphine and the other lipophilic opioids (e.g., fentanyl) pass rapidly via the arachnoid granulations into venous and lymphatic vessels, resulting in a minimal increase in cerebrospinal fluid concentration and risk of respiratory depression [5]. The greater duration of analgesia by buprenorphine than by other lipophilic drugs is generally attributed to its high affinity for opioid receptors [6]. That is why we decided to use buprenorphine rather than morphine and fentanyl in the intrathecal administration. Phantom limb pain immediately after amputation may be due to changes in the spinal cord, or even more rostral structures, somehow triggered by the sudden absence of nerve signals from the periphery. Another plausible explanation is that a massive discharge of axons at the time of injury or amputation leads to central changes that generate the report of pain [7]. Although it is believed that systemically administered opioid analgesics seldom benefit these patients, Jacobson et al. [8] published two case reports showing that intrathecal fentanyl had been dramatically effective for acute and persistent stump pain after amputation and phantom limb pain. This response, presumably to the spinal effects of opioids, suggested an important role for the spinal cord. After transection of a peripheral nerve, neurophysiologic changes occur in the spinal cord in the regions where opioid receptors are densely concentrated [9]. In our cases, intrathecally administered buprenorphine produced effective analgesia in phantom limb pain and stump pain. Therefore, an interaction of buprenorphine and opioid receptors in the spinal cord seems likely. We think the pain should be completely suppressed for some time, because the neural hyperexcitability (neuroplasticity) induced by the amputation needs to be changed in order to restore the normal neuronal transmission. The intrathecal buprenorphine was very effective in these cases, and therefore, we thought that intrathecal buprenorphine should be performed several times to suppress the hyperexcitability of the spinal nociceptive neurons for a period of at least 2 wk. In our two cases, the epidural block with bupivacaine was not satisfactory because the duration of effectiveness was short and because the pain reappeared when the injection of local anesthetic was discontinued. Not only was intrathecal buprenorphine superior to epidural bupivacaine from the viewpoint of long duration of analgesic effect in our cases, but spinal buprenorphine did not cause the motor and sensory effects noted with spinally administered local anesthetics. Intrathecal buprenorphine also increased the temperature of the lower part of the body in these cases. Since this was seen as early as 5-10 min after the intrathecal administration, it is likely that this hyperthermic effect was mediated through the spinal opioid receptors. Little is known of the mechanism of this phenomenon, but candidates include the sympathetic nervous system and the thermoregulatory center. Preganglionic nerve terminals [10] and the soma of sympathetic preganglionic neurons [11] contain opioid peptides. The effects of opioids on the sympathetic nervous system and sympathetically maintained pain are controversial [12-16]; it has been suggested that opioids injected around the stellate ganglion would give longer lasting relief in some patients than would local anesthetics [12-14], while others have found that pain of sympathetic origin was morphine insensitive [15,16]. There are also conflicting data on the effects of intrathecal opioids on body temperature. Although Rudy and Yaksh [17] have stated that intrathecally administered morphine dose-dependently produced a hyperthermic effect reversible with naloxone, other reports have shown that intrathecal morphine intensified the hypothermic action of spinal anesthesia in parturients [18], and that epidural sufentanil produced hypothermia [19]. Although the hypothalamus has the most control over temperature, the thermosensitive neurons in the ascending anterolateral tract of the spinal cord are also important; animal experiments showed that these are functionally as effective as the hypothalamic sensors [20]. Morphine exerts a direct, pharmacologically specific effect on the spinal cord which alters the thermoregulatory set point in the rat [17]. Thus, the increased temperature in the lower part of the body was probably produced by the sympathetic inhibitory effects or the effects on the spinal thermoregulatory system. Another possible mechanism might be the local anesthetic effects of buprenorphine, because fentanyl and meperidine show the local anesthetic effects in vitro [21]. However, because the increased temperatures were observed for more than 4 days in both cases, it does not seem that this increase is caused only by the local anesthetic effects of buprenorphine. We conclude that, in our patients with phantom limb pain, intrathecal buprenorphine demonstrated not only potent and long-lasting analgesic action, but also increased the temperature of the lower body. It is hoped that these current case reports will stimulate research into the utility of buprenorphine for patients who suffer from intractable phantom limb and stump pain.