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A case of uncommon withdrawal symptoms after a short period of spinal morphine administration
Pain, 64 (1996) 589-591
589
© 1996 Elsevier Science B.V. ~dl rights reserved 0304-3959/96/$15.00
PAIN 2976
Clinical Notes A case of uncommon withdrawal symptoms after a short period of spinal morphine administration Jacques Devulder *, Peter Bohyn, Fr6d6ric Castille, Martine De Laat and Georges Rolly Department of Anaesthesia, Section Pain Clinic, University Hospital of Gent, De Pintelaan 185, 9000 Gent (Belgium) (Received 19 January 1995, revised version received 24 April 1995, accepted 30 July 1995)
Summary A 54-year-old female with chronic failed back surgery syndrome and pain in the back and the right leg was treated by chronic spinal morphine administration by an external pump. After a positive test instillation over a 3-week period the spinal catheter was removed. Within 24 h the patient developed fever, leucocytosis, impaired sense of smell and allodynia and hyperpathia in all 4 limbs. Infection was excluded as a possible cause and a withdrawal after a second test period some weeks later reinitiated the symptoms. The symptoms vanished after restarting the morphine administration. Finally, an internal Medtronic pump was implanted because the patient obtained good pain relief with the test instillation. Good pain relief could be obtained with the daily instillation of 5 mg morphine intrathecally. Fever, leucocytosis, impaired sense of smell, allodynia and hyperpathia in the limbs reappeared a few weeks later. Evaluation showed catheter migration out of the spinal canal. Key words: Intrathecal morphine; Morphine withdrawal; Chronic pain
Introduction Chronic lumbosciatic pain following multiple surgical therapy is a well-latown chronic pain syndrome. Pain may be very resistant to therapy despite intensive treatment. Because of the failure of different therapeutic strategies sometimes chronic instillation of intrathecal morphine remains the last resort. Before implantation of a permanent pump and intrathecal catheter system, a positive test period with an external pump should be experienced. In single blind fashion the clinical effects of intrathecal morphine should be tested and compared with intrathecal saline. In our institution a test period of 3-4 weeks has been found to be useful. We report unusual withdrawal signs after a successful test period. Different reports about withdrawal signs after the use of spinal opioids have been reported, especially in animals, but not in humans (Marshall and Buccafusco 1985; Cridland et al. 1991; Jaffe 1992; Cruz and Villarreal 1993). The."withdrawal signs described by the patient were reproduced during a second test peCorresponding author: J. Devulder, M.D., Department of Anaesthesia, Section Pain Clinic, University Hospital of Gent, De Pintelaan 185, 9000 Gent, Belgium.
SSDI 0 3 0 4 - 3 9 5 9 ( 9 5 ) 0 0 1 8 7 - 5
riod as well after implantation of the permanent pump. The latter episode of withdrawal occurred because of catheter displacement out of the spinal canal a few weeks later.
Case report A 54-year-old female with chronic failed back surgery syndrome underwent a test period of chronic spinal morphine administration by pump. Previously she underwent back surgery for a disk herniating at the L4/L5 level. Her pain complaints remained the same even after a second surgical intervention with lysis of the adhesions at the L5 nerve root. A L 4 / L 5 / S I spinal fusion did not bring relief either. The patient's main complaint was of a burning and sharp stabbing pain in the right side of the back with radiation in the distribution of the right L5 nerve root and accompanied by decreased sensation in that area. There was an absent right angle jerk. Knee reflexes were present and equal. The seated and supine straight leg raising was limited to 45°. Flexion and extension of the vertebral column was extremely painful and there was a diminished range of movement. Palpation of the paravertebral musculature was very painful and there were trigger points in the paravertebral, gluteal and the piriformis muscles. Different, invasive and non invasive treatments (epidural injections, trigger point injections, facetal joint infiltrations and infiltrations over the saero-iliac joints with steroid were tried without benefit. No further surgery was contemplated and the symptoms were felt to be due to fibrosis and neuropathy.
590 Pain ratings measured on a visual analogue scale (VAS) were 4/10 after rest but rose to 8/10 in the standing position. Although transcutaneous electrical nerve stimulation (TENS) could alleviate her pain during standing and walking this could not be used long term as she developed an intolerable skin irritation at the electrode sites. Spinal cord stimulation was unsuccessful as it was not possible to overlap the pain area with stimulation paresthesias. A trial of sustained release oral morphine (60 mg twice daily) did not decrease her pain. Obviously, a much higher morphine dose could have been tried but in our country legal problems may arise from using large doses of oral opioid for chronic non-malignant pain. Thus we proceeded with a therapeutic trial of spinal opioids although we recognise that Krames (1993a,b) has suggested that spinal opioids should only be considered if oral opioid treatment fails. The instillation of intrathecal saline did not evoke a placebo response. A daily dose of 3 mg of intrathecal morphine hydrochloride achieved 50% reduction in pain. She became pain-free even during movement, with a daily dose of 5 mg morphine intrathecally. Urine retention was the only side effect and this could be controlled with 15 mg of oral betanechol chloride daily. After the 3-week instillation period the test catheter (Perifix 420, Braun Melsungen AG) was removed. Within 24 h, she developed fever to 38.4°C, a mild leucocytosis to 12,600 W.B.C./mm 3, vomiting, diarrhea, a disturbance in the sense of smell, ataxia, allodynia and hyperpathia in all limbs. Touching the affected skin with a small brush produced painful paresthesias in the lower part of the body from the 10th thoracic level downwards. There was no increase of other inflammatory parameters. The withdrawal symptoms were treated with the continuous intravenous administration of 40 mg of morphine per day; a dose which corresponded to the earlier oral daily dose (60 mg morphine twice daily). However, pain relief was insufficient with this dose as the VAS remained at 5/10. After exclusion of infection by appropriate testing, a new test period of 3 weeks was undertaken at the patients request as she feared implantation of a permanent pump and possible addiction. With the patient's informed consent, a new trial of morphine therapy was initiated intravenously as well as spinally. In a single blind manner the patient received either a continuous infusion of 40 mg of morphine intravenously per 24 h or an intravenous infusion of saline. Saline did not give pain relief and after 2 days we started the intravenous morphine. The intravenous morphine was adjusted during a 5-day period. The withdrawal of intravenous morphine over a 48 h period only, led to a return of more pain, but no withdrawal signs. Next in a, single blind fashion, 5 mg of morphine or saline were administered intrathecally. As previously, saline did not yield pain relief but spinal morphine resulted in proper pain relief. Its withdrawal after 5 days of administration resulted in a return of the symptoms, mentioned previously within 24 h. Sublingual buprenorphine could temper the symptoms. After pump implantation (Medtronic Minneapolis), Pain was very well controlled with 5 mg of morphine intrathecally each day. However, she was readmitted to hospital after 7 weeks of successful pain control because of fever, leucocytosis, vomiting, diarrhea, disturbance of smell, ataxia and allodynia and hyperpathia in all 4 limbs. The pump was not malfunctioning and injection of contrast in the side-port of the pump showed that the catheter was no longer in the intrathecal space but was dislogded subcutaneously. After catheter reinsertion and restarting the pump by giving a bolus dose of 0.5 mg of morphine intrathecally, the symptoms disappeared.
Discussion T h i s case r e p o r t illustrates o p i o i d w i t h d r a w a l associa t e d with t h e use o f spinal m o r p h i n e . H o w e v e r , t h e symptoms seem are uncommon. Normally, withdrawal
w o u l d p r e s e n t as m o r p h i n e craving a n d s y m p a t h e t i c a l l y m e d i a t e d events such as h y p e r t e n s i o n , t a c h y c a r d i a , sweating, l a c r i m a t i o n , p u p i l l a r y dilation, d i a r r h e a a n d h a l l u c i n a t i o n . O u r p a t i e n t d e v e l o p e d only a small inc r e a s e in b l o o d p r e s s u r e ( 1 1 0 / 7 0 m m H g to 1 4 0 / 8 0 m g Hg). T a c h y c a r d i a could n o t be o b s e r v e d as t h e p a t i e n t suffered from a chronic ventricular arrhythmia. T h e s y m p t o m s c o u l d b e b l o c k e d by systemic a d m i n i s t r a t i o n o f o p i o i d s b u t t h e y c o u l d n o t b e p r o v o k e d by its w i t h d r a w a l . T h e c o n t i n u o u s daily d o s e o f 40 m g i n t r a v e n o u s m o r p h i n e was p r o b a b l y small in c o m p a r i son with t h e 5 m g o f i n t r a t h e c a l m o r p h i n e . N e v e r t h e less, t h e p a i n r e l i e f d u r i n g t h e i n t r a v e n o u s m o r p h i n e a d m i n i s t r a t i o n p e r i o d was c o m p a r a b l e with t h a t b e e n during the second period of intrathecal morphine. It is r e m a r k a b l e t h a t t h e w i t h d r a w a l s y m p t o m s w e r e i d e n t i c a l o n e a c h o f t h r e e occasions a n d t h a t in t h e last two events t h e p a t i e n t was n o t a w a r e o f t h e c e s s a t i o n of m o r p h i n e t h e r a p y . It r e m a i n s very difficult to p r e d i c t in which p a t i e n t d e p e n d e n c y o r a d d i c t i o n o r w i t h d r a w a l signs will d e v e l o p ( F i s h b a i n et al. 1992; S e e r a n d C l a r k 1993). The, a d d i c t i o n r a t e for m o r p h i n e in c h r o n i c n o n - m a l i g n a n t p a i n has b e e n e s t i m a t e d to b e b e t w e e n 0.003% a n d 17% ( Z e n z et al. 1992). E s t i m a t i o n s o f t h e i n c i d e n c e for s y m p t o m s o f withd r a w a l a r e far m o r e difficult to obtain. I n d e e d , in o u r p a t i e n t s y m p t o m s c o u l d n o t b e a t t r i b u t e d to a d d i c t i o n b u t to physical a b s t i n e n c e . A f t e r c e s s a t i o n of m o r p h i n e t h e r a p y w e c o u l d n o t o b s e r v e a d r u g s e e k i n g behavior; on t h e c o n t r a r y t h e p a t i e n t felt ill. T h e s y m p t o m s o f vomiting, d i a r r h e a a n d t h e u n p l e a s a n t sense o f smell c o u l d b e c o n s i d e r e d as o r t h o s y m p a t h e t i c s t i m u l a t i o n effects r e s u l t i n g in hallucinations. T h e allodynia, h y p e r p a t h i a a n d ataxia a r e m o r e difficult to explain. In a p r e c i p i t a t e d w i t h d r a w a l test f r o m spinal m o r p h i n e c a r r i e d o u t using rats, fever a n d inc r e a s e d r e s p o n s i v e n e s s to n o c i c e p t i v e stimuli have b e e n d e s c r i b e d ( C r i d l a n d et al. 1991). T h e s y m p t o m s d e s c r i b e d in this study w e r e d i f f e r e n t f r o m t h o s e associa t e d with w i t h d r a w a l in systemically d e p e n d a n t animals. T h e a u t h o r s s p e c u l a t e t h a t t h o s e s y m p t o m s c o u l d b e r e l a t e d to an i n c r e a s e in t h e firing o f d o r s a l h o r n n e u r o n s . This o p i n i o n was b a s e d u p o n an e l e v a t i o n o f m e t - e n k e p h a l i n in t h e l u m b a r a n d t h e sacral spinal r e g i o n a n d n o t in t h e b r a i n 24 h a f t e r spinal m o r p h i n e w i t h d r a w a l ( C r i d l a n d et al. 1991). U e d a s h o w e d by a n a l o x o n e c h a l l e n g e test in systemically m o r p h i n e - d e p e n d e n t mice a r e l e a s e o f spinal s u b s t a n c e P ( U e d a et al. 1987). It is q u i t e e v i d e n t b u t still s p e c u l a t i v e t h a t such r e l e a s e also m i g h t e x p l a i n d o r s a l h o r n excitation with a l l o d y n i a a n d h y p e r p a t h i a . M i l d h y p e r t h e r m i a a n d leucocytosis w i t h o u t inflamm a t i o n s e e m even m o r e q u e s t i o n a b l e . T h e s e s y m p t o m s d o n o t reflect o r t h o s y m p a t h e t i c stimulation. Cribs also s h o w e d h y p e r t h e r m i a d u r i n g spinal w i t h d r a w a l al-
591
though others obtained the opposite result and saw hypothermia (Delander and Takemori 1983; Maynert and Klingman 1962). Hyperthermia was also noticed by Milne et al. (1985). They postulated that supraspinal mechanisms might play a role in these symptoms. This case report illustrates a particular form of withdrawal after as little as 5 days of intrathecal morphine. The mechanism remains unclear. This case report might re-open debate about chronic opioid therapy in nonmalignant pain (Portenoy 1990; Jamison and Anderson 1994; Krames 1993a). In the literature great fear exists concerning the creation of addiction in those patients using chronic opioids (Seer and Clark 1993). Long-term opioid therapy is well accepted for the management of cancer-:related pain but remains controversial for those with nonmalignant pain (Krames 1993a). The appropriate use of intrathecal morphine is even more controversial. In view of this Krames (1993a,b) advocates a sequential oral trial of opioid before starting spinal morphine. Caution seems indicated as long-term effects of intraspinal infusional therapy are unknown. Potential side effects such as polyarthralgia and sexual dysfunction have been described (Krames 1993b). In view of these potential problems, persevering with oral morphine treatment should be encouraged, instead of starting spinal opioids which may have severe side effects, and which is veuz expensive when the use of the implantable pump is indicated. The use of the oral route for opioid therapy would have avoided the episode of unintentionall withdrawal. References Cridland, R., Sutak, M. and 3hamandas, K., Characteristics of precipitated withdrawal from spinal morphine: changes in (Met)enkephalin levels, Eur. J. Pharmacol., 203 (1991) 93-103.
Cruz, S.L. and Villarreal, J.E., Acute opioid dependence in the cardiovascular system of the spinal rat, J. Pharmcol. Exp. Ther., 265 (1993) 128-133. Delander, G. and Takemori, A., Spinal antagonism of tolerance and dependence induced by systemically administered morphine, Eur. J. Pharmacol., 94 (1983) 35. Fishbain, D , Rosomoff, H. and Rosomoff, R., Drug abuse, dependence, and addiction in chronic pain patients, Clin. J. Pain, 8 (1992) 77-85. Jaffe, J., Opiates: Clinical Aspects in Substance Abuse: a Comprehensive Textbook. 2nd edn., Ch. 14, Lowin et al. (Eds.), Williams and Wilkins, Baltimore, MD, 1992, pp. 189-191. Jamison, R., Anderson, K., Peeters-Asdourian, C. and Ferrante, M., Survey of opioid use in chronic nonmalignant pain patients, Reg. Anesth., 19 (1994) 225-230. Krames, E., Intrathecal Infusional therapies for intractable pain: patient management guidelines, J. Pain Sympt. Manag., 8 (1993a) 36-46. Krames, E., The chronic intraspinal use of opioid and local anesthetic mixtures for the relief of intractable pain: when all else fails?, Pain, 55 (1993b) 1-4. Marshall, D.C., and Buccafusco, J.J., Supraspinal and spinal mediation of naloxone-induced morphine withdrawal in rats, Brain. Res., 329 (1985) 131-142. Maynert, E. and Klingman, G., Tolerance to morphine. Effects on catecholamines in the brain and adrenal glands, J. Pharmacol. Exp. Ther., 135 (1962) 285. Milne, B., Cervenko, F., Jhamandas, K. and Sutak, M., Intrathecal clonidine: analgesia and effect on opiate withdrawal in the rat, Anesthesiology, 62 (1985) 34. Paice, J., Penn, R. and Ryan, W., Altered sexual function and decreased testosterone in patients receiving intraspinal opioids J. Pain Sympt. Manag., 9 (1994) 126-131. Portenoy, R., Chronic opioid therapy in nonmalignant pain J. Pain Sympt. Manag., 5 (Suppl.) (1990) 46-62. Seers, K., and Clark, H., Opioid use in the treatment of chronic pain: assessment of addiction, J. Pain Sympt. Manag., 8 (1993) 257-264. Ueda, H., Tamura, S., Satoh, M. and Takagi, H., Excess release of substance P from the spinal cord of mice during morphine withdrawal and involvement of the enhancement of presynaptic calcium entry, Brain Res., 425 (1987) 101. Zenz, M., Strumpf, M. and Tryba, M., Long-term oral opioid therapy in patients with chronic nonmalignant pain, J. Pain Sympt. Manag., 7 (1992) 69-77.
589
© 1996 Elsevier Science B.V. ~dl rights reserved 0304-3959/96/$15.00
PAIN 2976
Clinical Notes A case of uncommon withdrawal symptoms after a short period of spinal morphine administration Jacques Devulder *, Peter Bohyn, Fr6d6ric Castille, Martine De Laat and Georges Rolly Department of Anaesthesia, Section Pain Clinic, University Hospital of Gent, De Pintelaan 185, 9000 Gent (Belgium) (Received 19 January 1995, revised version received 24 April 1995, accepted 30 July 1995)
Summary A 54-year-old female with chronic failed back surgery syndrome and pain in the back and the right leg was treated by chronic spinal morphine administration by an external pump. After a positive test instillation over a 3-week period the spinal catheter was removed. Within 24 h the patient developed fever, leucocytosis, impaired sense of smell and allodynia and hyperpathia in all 4 limbs. Infection was excluded as a possible cause and a withdrawal after a second test period some weeks later reinitiated the symptoms. The symptoms vanished after restarting the morphine administration. Finally, an internal Medtronic pump was implanted because the patient obtained good pain relief with the test instillation. Good pain relief could be obtained with the daily instillation of 5 mg morphine intrathecally. Fever, leucocytosis, impaired sense of smell, allodynia and hyperpathia in the limbs reappeared a few weeks later. Evaluation showed catheter migration out of the spinal canal. Key words: Intrathecal morphine; Morphine withdrawal; Chronic pain
Introduction Chronic lumbosciatic pain following multiple surgical therapy is a well-latown chronic pain syndrome. Pain may be very resistant to therapy despite intensive treatment. Because of the failure of different therapeutic strategies sometimes chronic instillation of intrathecal morphine remains the last resort. Before implantation of a permanent pump and intrathecal catheter system, a positive test period with an external pump should be experienced. In single blind fashion the clinical effects of intrathecal morphine should be tested and compared with intrathecal saline. In our institution a test period of 3-4 weeks has been found to be useful. We report unusual withdrawal signs after a successful test period. Different reports about withdrawal signs after the use of spinal opioids have been reported, especially in animals, but not in humans (Marshall and Buccafusco 1985; Cridland et al. 1991; Jaffe 1992; Cruz and Villarreal 1993). The."withdrawal signs described by the patient were reproduced during a second test peCorresponding author: J. Devulder, M.D., Department of Anaesthesia, Section Pain Clinic, University Hospital of Gent, De Pintelaan 185, 9000 Gent, Belgium.
SSDI 0 3 0 4 - 3 9 5 9 ( 9 5 ) 0 0 1 8 7 - 5
riod as well after implantation of the permanent pump. The latter episode of withdrawal occurred because of catheter displacement out of the spinal canal a few weeks later.
Case report A 54-year-old female with chronic failed back surgery syndrome underwent a test period of chronic spinal morphine administration by pump. Previously she underwent back surgery for a disk herniating at the L4/L5 level. Her pain complaints remained the same even after a second surgical intervention with lysis of the adhesions at the L5 nerve root. A L 4 / L 5 / S I spinal fusion did not bring relief either. The patient's main complaint was of a burning and sharp stabbing pain in the right side of the back with radiation in the distribution of the right L5 nerve root and accompanied by decreased sensation in that area. There was an absent right angle jerk. Knee reflexes were present and equal. The seated and supine straight leg raising was limited to 45°. Flexion and extension of the vertebral column was extremely painful and there was a diminished range of movement. Palpation of the paravertebral musculature was very painful and there were trigger points in the paravertebral, gluteal and the piriformis muscles. Different, invasive and non invasive treatments (epidural injections, trigger point injections, facetal joint infiltrations and infiltrations over the saero-iliac joints with steroid were tried without benefit. No further surgery was contemplated and the symptoms were felt to be due to fibrosis and neuropathy.
590 Pain ratings measured on a visual analogue scale (VAS) were 4/10 after rest but rose to 8/10 in the standing position. Although transcutaneous electrical nerve stimulation (TENS) could alleviate her pain during standing and walking this could not be used long term as she developed an intolerable skin irritation at the electrode sites. Spinal cord stimulation was unsuccessful as it was not possible to overlap the pain area with stimulation paresthesias. A trial of sustained release oral morphine (60 mg twice daily) did not decrease her pain. Obviously, a much higher morphine dose could have been tried but in our country legal problems may arise from using large doses of oral opioid for chronic non-malignant pain. Thus we proceeded with a therapeutic trial of spinal opioids although we recognise that Krames (1993a,b) has suggested that spinal opioids should only be considered if oral opioid treatment fails. The instillation of intrathecal saline did not evoke a placebo response. A daily dose of 3 mg of intrathecal morphine hydrochloride achieved 50% reduction in pain. She became pain-free even during movement, with a daily dose of 5 mg morphine intrathecally. Urine retention was the only side effect and this could be controlled with 15 mg of oral betanechol chloride daily. After the 3-week instillation period the test catheter (Perifix 420, Braun Melsungen AG) was removed. Within 24 h, she developed fever to 38.4°C, a mild leucocytosis to 12,600 W.B.C./mm 3, vomiting, diarrhea, a disturbance in the sense of smell, ataxia, allodynia and hyperpathia in all limbs. Touching the affected skin with a small brush produced painful paresthesias in the lower part of the body from the 10th thoracic level downwards. There was no increase of other inflammatory parameters. The withdrawal symptoms were treated with the continuous intravenous administration of 40 mg of morphine per day; a dose which corresponded to the earlier oral daily dose (60 mg morphine twice daily). However, pain relief was insufficient with this dose as the VAS remained at 5/10. After exclusion of infection by appropriate testing, a new test period of 3 weeks was undertaken at the patients request as she feared implantation of a permanent pump and possible addiction. With the patient's informed consent, a new trial of morphine therapy was initiated intravenously as well as spinally. In a single blind manner the patient received either a continuous infusion of 40 mg of morphine intravenously per 24 h or an intravenous infusion of saline. Saline did not give pain relief and after 2 days we started the intravenous morphine. The intravenous morphine was adjusted during a 5-day period. The withdrawal of intravenous morphine over a 48 h period only, led to a return of more pain, but no withdrawal signs. Next in a, single blind fashion, 5 mg of morphine or saline were administered intrathecally. As previously, saline did not yield pain relief but spinal morphine resulted in proper pain relief. Its withdrawal after 5 days of administration resulted in a return of the symptoms, mentioned previously within 24 h. Sublingual buprenorphine could temper the symptoms. After pump implantation (Medtronic Minneapolis), Pain was very well controlled with 5 mg of morphine intrathecally each day. However, she was readmitted to hospital after 7 weeks of successful pain control because of fever, leucocytosis, vomiting, diarrhea, disturbance of smell, ataxia and allodynia and hyperpathia in all 4 limbs. The pump was not malfunctioning and injection of contrast in the side-port of the pump showed that the catheter was no longer in the intrathecal space but was dislogded subcutaneously. After catheter reinsertion and restarting the pump by giving a bolus dose of 0.5 mg of morphine intrathecally, the symptoms disappeared.
Discussion T h i s case r e p o r t illustrates o p i o i d w i t h d r a w a l associa t e d with t h e use o f spinal m o r p h i n e . H o w e v e r , t h e symptoms seem are uncommon. Normally, withdrawal
w o u l d p r e s e n t as m o r p h i n e craving a n d s y m p a t h e t i c a l l y m e d i a t e d events such as h y p e r t e n s i o n , t a c h y c a r d i a , sweating, l a c r i m a t i o n , p u p i l l a r y dilation, d i a r r h e a a n d h a l l u c i n a t i o n . O u r p a t i e n t d e v e l o p e d only a small inc r e a s e in b l o o d p r e s s u r e ( 1 1 0 / 7 0 m m H g to 1 4 0 / 8 0 m g Hg). T a c h y c a r d i a could n o t be o b s e r v e d as t h e p a t i e n t suffered from a chronic ventricular arrhythmia. T h e s y m p t o m s c o u l d b e b l o c k e d by systemic a d m i n i s t r a t i o n o f o p i o i d s b u t t h e y c o u l d n o t b e p r o v o k e d by its w i t h d r a w a l . T h e c o n t i n u o u s daily d o s e o f 40 m g i n t r a v e n o u s m o r p h i n e was p r o b a b l y small in c o m p a r i son with t h e 5 m g o f i n t r a t h e c a l m o r p h i n e . N e v e r t h e less, t h e p a i n r e l i e f d u r i n g t h e i n t r a v e n o u s m o r p h i n e a d m i n i s t r a t i o n p e r i o d was c o m p a r a b l e with t h a t b e e n during the second period of intrathecal morphine. It is r e m a r k a b l e t h a t t h e w i t h d r a w a l s y m p t o m s w e r e i d e n t i c a l o n e a c h o f t h r e e occasions a n d t h a t in t h e last two events t h e p a t i e n t was n o t a w a r e o f t h e c e s s a t i o n of m o r p h i n e t h e r a p y . It r e m a i n s very difficult to p r e d i c t in which p a t i e n t d e p e n d e n c y o r a d d i c t i o n o r w i t h d r a w a l signs will d e v e l o p ( F i s h b a i n et al. 1992; S e e r a n d C l a r k 1993). The, a d d i c t i o n r a t e for m o r p h i n e in c h r o n i c n o n - m a l i g n a n t p a i n has b e e n e s t i m a t e d to b e b e t w e e n 0.003% a n d 17% ( Z e n z et al. 1992). E s t i m a t i o n s o f t h e i n c i d e n c e for s y m p t o m s o f withd r a w a l a r e far m o r e difficult to obtain. I n d e e d , in o u r p a t i e n t s y m p t o m s c o u l d n o t b e a t t r i b u t e d to a d d i c t i o n b u t to physical a b s t i n e n c e . A f t e r c e s s a t i o n of m o r p h i n e t h e r a p y w e c o u l d n o t o b s e r v e a d r u g s e e k i n g behavior; on t h e c o n t r a r y t h e p a t i e n t felt ill. T h e s y m p t o m s o f vomiting, d i a r r h e a a n d t h e u n p l e a s a n t sense o f smell c o u l d b e c o n s i d e r e d as o r t h o s y m p a t h e t i c s t i m u l a t i o n effects r e s u l t i n g in hallucinations. T h e allodynia, h y p e r p a t h i a a n d ataxia a r e m o r e difficult to explain. In a p r e c i p i t a t e d w i t h d r a w a l test f r o m spinal m o r p h i n e c a r r i e d o u t using rats, fever a n d inc r e a s e d r e s p o n s i v e n e s s to n o c i c e p t i v e stimuli have b e e n d e s c r i b e d ( C r i d l a n d et al. 1991). T h e s y m p t o m s d e s c r i b e d in this study w e r e d i f f e r e n t f r o m t h o s e associa t e d with w i t h d r a w a l in systemically d e p e n d a n t animals. T h e a u t h o r s s p e c u l a t e t h a t t h o s e s y m p t o m s c o u l d b e r e l a t e d to an i n c r e a s e in t h e firing o f d o r s a l h o r n n e u r o n s . This o p i n i o n was b a s e d u p o n an e l e v a t i o n o f m e t - e n k e p h a l i n in t h e l u m b a r a n d t h e sacral spinal r e g i o n a n d n o t in t h e b r a i n 24 h a f t e r spinal m o r p h i n e w i t h d r a w a l ( C r i d l a n d et al. 1991). U e d a s h o w e d by a n a l o x o n e c h a l l e n g e test in systemically m o r p h i n e - d e p e n d e n t mice a r e l e a s e o f spinal s u b s t a n c e P ( U e d a et al. 1987). It is q u i t e e v i d e n t b u t still s p e c u l a t i v e t h a t such r e l e a s e also m i g h t e x p l a i n d o r s a l h o r n excitation with a l l o d y n i a a n d h y p e r p a t h i a . M i l d h y p e r t h e r m i a a n d leucocytosis w i t h o u t inflamm a t i o n s e e m even m o r e q u e s t i o n a b l e . T h e s e s y m p t o m s d o n o t reflect o r t h o s y m p a t h e t i c stimulation. Cribs also s h o w e d h y p e r t h e r m i a d u r i n g spinal w i t h d r a w a l al-
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though others obtained the opposite result and saw hypothermia (Delander and Takemori 1983; Maynert and Klingman 1962). Hyperthermia was also noticed by Milne et al. (1985). They postulated that supraspinal mechanisms might play a role in these symptoms. This case report illustrates a particular form of withdrawal after as little as 5 days of intrathecal morphine. The mechanism remains unclear. This case report might re-open debate about chronic opioid therapy in nonmalignant pain (Portenoy 1990; Jamison and Anderson 1994; Krames 1993a). In the literature great fear exists concerning the creation of addiction in those patients using chronic opioids (Seer and Clark 1993). Long-term opioid therapy is well accepted for the management of cancer-:related pain but remains controversial for those with nonmalignant pain (Krames 1993a). The appropriate use of intrathecal morphine is even more controversial. In view of this Krames (1993a,b) advocates a sequential oral trial of opioid before starting spinal morphine. Caution seems indicated as long-term effects of intraspinal infusional therapy are unknown. Potential side effects such as polyarthralgia and sexual dysfunction have been described (Krames 1993b). In view of these potential problems, persevering with oral morphine treatment should be encouraged, instead of starting spinal opioids which may have severe side effects, and which is veuz expensive when the use of the implantable pump is indicated. The use of the oral route for opioid therapy would have avoided the episode of unintentionall withdrawal. References Cridland, R., Sutak, M. and 3hamandas, K., Characteristics of precipitated withdrawal from spinal morphine: changes in (Met)enkephalin levels, Eur. J. Pharmacol., 203 (1991) 93-103.
Cruz, S.L. and Villarreal, J.E., Acute opioid dependence in the cardiovascular system of the spinal rat, J. Pharmcol. Exp. Ther., 265 (1993) 128-133. Delander, G. and Takemori, A., Spinal antagonism of tolerance and dependence induced by systemically administered morphine, Eur. J. Pharmacol., 94 (1983) 35. Fishbain, D , Rosomoff, H. and Rosomoff, R., Drug abuse, dependence, and addiction in chronic pain patients, Clin. J. Pain, 8 (1992) 77-85. Jaffe, J., Opiates: Clinical Aspects in Substance Abuse: a Comprehensive Textbook. 2nd edn., Ch. 14, Lowin et al. (Eds.), Williams and Wilkins, Baltimore, MD, 1992, pp. 189-191. Jamison, R., Anderson, K., Peeters-Asdourian, C. and Ferrante, M., Survey of opioid use in chronic nonmalignant pain patients, Reg. Anesth., 19 (1994) 225-230. Krames, E., Intrathecal Infusional therapies for intractable pain: patient management guidelines, J. Pain Sympt. Manag., 8 (1993a) 36-46. Krames, E., The chronic intraspinal use of opioid and local anesthetic mixtures for the relief of intractable pain: when all else fails?, Pain, 55 (1993b) 1-4. Marshall, D.C., and Buccafusco, J.J., Supraspinal and spinal mediation of naloxone-induced morphine withdrawal in rats, Brain. Res., 329 (1985) 131-142. Maynert, E. and Klingman, G., Tolerance to morphine. Effects on catecholamines in the brain and adrenal glands, J. Pharmacol. Exp. Ther., 135 (1962) 285. Milne, B., Cervenko, F., Jhamandas, K. and Sutak, M., Intrathecal clonidine: analgesia and effect on opiate withdrawal in the rat, Anesthesiology, 62 (1985) 34. Paice, J., Penn, R. and Ryan, W., Altered sexual function and decreased testosterone in patients receiving intraspinal opioids J. Pain Sympt. Manag., 9 (1994) 126-131. Portenoy, R., Chronic opioid therapy in nonmalignant pain J. Pain Sympt. Manag., 5 (Suppl.) (1990) 46-62. Seers, K., and Clark, H., Opioid use in the treatment of chronic pain: assessment of addiction, J. Pain Sympt. Manag., 8 (1993) 257-264. Ueda, H., Tamura, S., Satoh, M. and Takagi, H., Excess release of substance P from the spinal cord of mice during morphine withdrawal and involvement of the enhancement of presynaptic calcium entry, Brain Res., 425 (1987) 101. Zenz, M., Strumpf, M. and Tryba, M., Long-term oral opioid therapy in patients with chronic nonmalignant pain, J. Pain Sympt. Manag., 7 (1992) 69-77.