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The use of the opiate antagonist, naloxone, in the treatment of intractable pain
Veuropeptides 5- 419-422, 1985
THE USE OF THE OPIATE ANTAGONIST, NALOXONE, IN THE TREATMENT OF INTRACTABLE PAIN Dr. Keith Budd Royal Infirmary
Bradford BD9 6RJ
U.K.
Summary: Thirteen adult patients with established thalamic syndrome, resistant to prior analgesic and other therapy, were treated with intraA total of twenty venous infusions of the opiate antagonist, naloxone. treatments were administered with doses of naloxone varying from 4.0 3.0 mgs. 3even patients exhibited beneficial effects with the duration of the resultant pain relief ranging from four days to two and a half years. In these patients, pain and hyperpathia were completely obtunded in six Side effects of therapy were out of seven and partially in one. minimal and of short duration being mainly confined to the cardioDuring therapy all patients had continuous E.C.G. vascular system. monitoring. In certain ischaemic conditions of the central nervous system, endogenous opioids possibly reduce cerebral blood flow via. inhibition of the locus coeruleus and subsequent releaseof noradrenaline: hence naloxone by inhibiting the opioids could increase cerebral perfusion pressure. This study has shown the benefit of treating patients with cerebral ischaemic lesions with an opioid antagonist. The rapidity of onset of pain relief in these patients would appear to indicate a mode of action by increasing cerebral perfusion. Introduction The thalamic syndrome, first described by Dejerine and Roussy (1) is one of the more distressing complications of cerebra-vascular accidents. Severe pain is usually cited by patients as the most incapacitating characteristic of their post-stroke syndrome, residual hemiparesis, hemianaesthesia, hemiataxia and choreoathetoid movements when present seeming both collectively and individually less throublesome than the more pronounced dysaesthetic manifestations and pain. The pathology of the thalamus is largely determined by its blood supply which is from the posterior cerebral artery by way of the thalamogeniculate and thalamo-perforating arteries. If the thalamo-geniculate artery alone is involved in a thrombotic episode, the normal components of the thalamic syndrome will develop, namely a transient, flaccid hemiparesis or hemiplegia followed by permanent impairment of superficial and loss of deep sensation; agonizing, burning pain and choreoathetotic movements, ataxia and tremor affecting the side opposite the lesion. The threshold to sensory stimuli is usually raised on the affected side bl 419
such stimuli, when they become effective, can excite unpleasant sensations. If the main trunk of the posterior cerebral artery is thrombosed both the thalamus and the occipital lobe will be affected and thalamic syndrome Thrombosis of together with an homonymous hemianopia will be present. smaller arterial branches may give rise to parts of these syndromes. Occasionally, particularly in the younger age group, very limited lesions of the posterior thalamus may present with headache and no other associated symptoms and signs. Although cases of thalamic syndrome may undergo spontaneous remission, the severity and persistence of symptoms usually emphasises the need for Most cases are, however, refractory to treatment with active therapy. primary analgesics and from amongst the secondary analgesics, anticonvulsants such as phenytoin and carbamazepine have enjoyed the greatest success (2). Surgery in the form of sterotactic thalamotomy or mesencephalotomy has little to offer because of very limited duration of effect although electrical stimulation of the internal capsule on the damaged side has shown some benefit. The opioid antagonist, naloxone, has been shown to improve recovery from a variety of ischaemic lesions within the central nervous system, not only decreasing neurological impairment following spinal injury (3,4) but also reversing experimental hemiplegia and hemiparesis in primates (5). Clinical reports from a number of workers have indicated that naloxone has produced partial or complete reversal of neurological deficits following cerebral ischaemia, (6) possibly by increasing blood flow to ischaemic areas of brain thereby limiting neurological injury. Method The group chosen for study were adults with independently diagnosed classical thalamic syndrome. All had received prior ineffective therapy with both primary and secondary analgesic agents. Naloxone was administered intravenously in 0.4 mg. aliquots over the course of lo-15 minutes until either a response was obtained or the designated ceiling level (8 mgs. reached). During drug administration continuous patient E.C.G. monitoring was carried out because of the possibility of cardiovascular side effects (8). Any change in pain state was ascertained by direct questioning of the patient after the giving of each aliquot of naloxone. Results. Thirteen patients were studied who received a total of 20 naloxone administrations. Eight patients were male, mean age 62 years (range 58-78 years) and five female, mean age 67 years (56-72 years). Onset of pain and hyperpathia following the stroke varied from immediate to six months and the interval from the onset of pain to therapy varied from two months to one year. Eight patients had pain affecting the right side of the body (6 dominant, 2 non-dominant) and five the left side (1 dominant, 4 non-dominant). 420
Patient No. 1
Sex
M
Age -
Affected Part
CVA-treatment interval
62
L.Arm & Leg
3 months
2 3 4
F F M
70 68 60
R.Arm R.Arm L.Side
6 months 4 months 1 year
5 6
F M
56 58
3 months 3 months
7
M
60
8
F
72
9 10
M M
61 78
I.1
F
69
R.Side R.Arm & Leg L.Arm & Leg R.Arm & Leg R.Arm L.Arm & Leg R.Arm
12
M
61
7 months
13
M
58
L-Arm & Leg R.Arm & Leg
Dose Naloxone
Duration of Relief
4 mgs. 8 mgs.
6 weeks
3.6 4.4 4 8 8 8 8
mgs. mgs. mgs. mgs. mgs. mgs. mgs.
2 months
3.2 mgs. 8 mgs. 8 mgs.
6 months 7 months
8 mgs. 8 mgs.
9 months
4 8 4 8 4 8
6 months
11 months
mgs. mgs. mgs. mgs. mgs. mgs.
2 2 3 6 1 2
years weeks weeks months year years
4 months 2% years
-
4 days
Seven patients exhibited a beneficial response to naloxone with duration Six patients of effect varying from four days to two and a half years. failed to respond to a maximum dose of 8 mgs. Inthose who responded, pain and hyperpathia was completely obtunded in six patients and partially in one, this partial effect lasting four days with no response to a subsequent maximal dose, All changes in clinical state were apparent within five minutes of the completion of naloxone administration. Side Effects All patients were observed to have an increase in'heart rate of lo-40 beats/min. over resting after the administration of naloxone: The degree of tachycardia was not dose related. Three patients exhibited a rise of more than 10 mm Hg over resting systolic blood pressure with naloxone and one a fall of 20 mm Hg over resting systolic. All changes were transitory lasting no longer than five minutes after the termination of naloxone administration. Apart from changes in rate, no alterations in E.C.G. patterns were seen. Transient dizzyness was seen in two patients, unrelated to any change in blood pressure. Discussion In ischaemic disease of the central nervous system, endogenous opioids, 421
whose titre in the cerebra-spinal fluid of these patients is increased, possibly reduce cerebral blood flow by inhibition of the locus coeruleus, this latter being an important activator of cerebra-vascular tone through the release of noradrenaline (8). Naloxone could, therefore, by antagonising the opioid effect increase vessel tone and cerebral vascular perfusion pressure. This effect is apparent in patients with ischaemic limbs in whom vascular perfusion and limb temperature can be increased by the administration of naloxone. The results presented here are not isolated findings and independent studies confirm both the beneficial effect of naloxone in thalamic syndrome and this not being due to placebo effect. The speed of onset of the analgesic effect would seem to indicate a vascular phenomenon and although initial studies with naloxone did indicate some analgesic effect (9) it is doubtful that the findings of this study confirm an effect via the accepted receptor sites. Conclusion. In patients with thalamic syndrome, naloxone administered intravenously was shown to produce a lasting beneficial effect in 54% of the trial population and exhibited as deleterious side effects. References.
(1)
Le syndrome thalamique. DEJERINE J., ROUSSY G. (1906) Revue Neurologique. 14., 521-532.
(2)
AGNEW D.C., GOLDBERG V.A. (1976) A brief trial of phenytoin therapy for thalamic pain. Bulletin Los Angeles Neurological Society. 41., 9.
(3)
FADEN A.I., JACOBS T.P., HOLADAY J.W. (1981) Opiate antagonist improves neurologic recovery after spinal injury. Science. 211., 493-494.
(4)
YOUNG W., FLAMM E.S., DEMOPOULOS H.G., TOMASULA J.H., DECRESCITO V., (1981) Effect of naloxone on post traumatic ischaemia in experimental spinal contusion. Journal of Neurosurgery. 55., 209-219.
(5)
BASKIN D.S., KIECK C.F., HOSOBUCHI Y. (1982) Naloxone reversal of ischaemic neurological deficits in baboons is not mediated by systemic effects. Life Sciences. 31., 2201-2204.
(6)
BASKIN D.S., HOSOBUCHI Y. (1981) neurological deficits in man. Lancet. 2., 272-275.
(7)
CUSS F.M., COLACO C.B., BARON J.H. (1984) Cardiac arrest after reversal of effects of opiates with naloxone. British Medical Journal. 288., 363-364.
(8)
STRAHLENDORF H.K., STRAHLENDORF J.C., BARNES C.D. (1980) Endorphin mediated inhibition of locus coeruleus neurons. Brain Research. 191., 284-288.
(9)
LASAGNA L. (1965) Drug interaction in the field of analgesic drugs. Proceedings of the Royal Society of Medicine. 58., 978-985. 422
Naloxone reversal of ischaemic
THE USE OF THE OPIATE ANTAGONIST, NALOXONE, IN THE TREATMENT OF INTRACTABLE PAIN Dr. Keith Budd Royal Infirmary
Bradford BD9 6RJ
U.K.
Summary: Thirteen adult patients with established thalamic syndrome, resistant to prior analgesic and other therapy, were treated with intraA total of twenty venous infusions of the opiate antagonist, naloxone. treatments were administered with doses of naloxone varying from 4.0 3.0 mgs. 3even patients exhibited beneficial effects with the duration of the resultant pain relief ranging from four days to two and a half years. In these patients, pain and hyperpathia were completely obtunded in six Side effects of therapy were out of seven and partially in one. minimal and of short duration being mainly confined to the cardioDuring therapy all patients had continuous E.C.G. vascular system. monitoring. In certain ischaemic conditions of the central nervous system, endogenous opioids possibly reduce cerebral blood flow via. inhibition of the locus coeruleus and subsequent releaseof noradrenaline: hence naloxone by inhibiting the opioids could increase cerebral perfusion pressure. This study has shown the benefit of treating patients with cerebral ischaemic lesions with an opioid antagonist. The rapidity of onset of pain relief in these patients would appear to indicate a mode of action by increasing cerebral perfusion. Introduction The thalamic syndrome, first described by Dejerine and Roussy (1) is one of the more distressing complications of cerebra-vascular accidents. Severe pain is usually cited by patients as the most incapacitating characteristic of their post-stroke syndrome, residual hemiparesis, hemianaesthesia, hemiataxia and choreoathetoid movements when present seeming both collectively and individually less throublesome than the more pronounced dysaesthetic manifestations and pain. The pathology of the thalamus is largely determined by its blood supply which is from the posterior cerebral artery by way of the thalamogeniculate and thalamo-perforating arteries. If the thalamo-geniculate artery alone is involved in a thrombotic episode, the normal components of the thalamic syndrome will develop, namely a transient, flaccid hemiparesis or hemiplegia followed by permanent impairment of superficial and loss of deep sensation; agonizing, burning pain and choreoathetotic movements, ataxia and tremor affecting the side opposite the lesion. The threshold to sensory stimuli is usually raised on the affected side bl 419
such stimuli, when they become effective, can excite unpleasant sensations. If the main trunk of the posterior cerebral artery is thrombosed both the thalamus and the occipital lobe will be affected and thalamic syndrome Thrombosis of together with an homonymous hemianopia will be present. smaller arterial branches may give rise to parts of these syndromes. Occasionally, particularly in the younger age group, very limited lesions of the posterior thalamus may present with headache and no other associated symptoms and signs. Although cases of thalamic syndrome may undergo spontaneous remission, the severity and persistence of symptoms usually emphasises the need for Most cases are, however, refractory to treatment with active therapy. primary analgesics and from amongst the secondary analgesics, anticonvulsants such as phenytoin and carbamazepine have enjoyed the greatest success (2). Surgery in the form of sterotactic thalamotomy or mesencephalotomy has little to offer because of very limited duration of effect although electrical stimulation of the internal capsule on the damaged side has shown some benefit. The opioid antagonist, naloxone, has been shown to improve recovery from a variety of ischaemic lesions within the central nervous system, not only decreasing neurological impairment following spinal injury (3,4) but also reversing experimental hemiplegia and hemiparesis in primates (5). Clinical reports from a number of workers have indicated that naloxone has produced partial or complete reversal of neurological deficits following cerebral ischaemia, (6) possibly by increasing blood flow to ischaemic areas of brain thereby limiting neurological injury. Method The group chosen for study were adults with independently diagnosed classical thalamic syndrome. All had received prior ineffective therapy with both primary and secondary analgesic agents. Naloxone was administered intravenously in 0.4 mg. aliquots over the course of lo-15 minutes until either a response was obtained or the designated ceiling level (8 mgs. reached). During drug administration continuous patient E.C.G. monitoring was carried out because of the possibility of cardiovascular side effects (8). Any change in pain state was ascertained by direct questioning of the patient after the giving of each aliquot of naloxone. Results. Thirteen patients were studied who received a total of 20 naloxone administrations. Eight patients were male, mean age 62 years (range 58-78 years) and five female, mean age 67 years (56-72 years). Onset of pain and hyperpathia following the stroke varied from immediate to six months and the interval from the onset of pain to therapy varied from two months to one year. Eight patients had pain affecting the right side of the body (6 dominant, 2 non-dominant) and five the left side (1 dominant, 4 non-dominant). 420
Patient No. 1
Sex
M
Age -
Affected Part
CVA-treatment interval
62
L.Arm & Leg
3 months
2 3 4
F F M
70 68 60
R.Arm R.Arm L.Side
6 months 4 months 1 year
5 6
F M
56 58
3 months 3 months
7
M
60
8
F
72
9 10
M M
61 78
I.1
F
69
R.Side R.Arm & Leg L.Arm & Leg R.Arm & Leg R.Arm L.Arm & Leg R.Arm
12
M
61
7 months
13
M
58
L-Arm & Leg R.Arm & Leg
Dose Naloxone
Duration of Relief
4 mgs. 8 mgs.
6 weeks
3.6 4.4 4 8 8 8 8
mgs. mgs. mgs. mgs. mgs. mgs. mgs.
2 months
3.2 mgs. 8 mgs. 8 mgs.
6 months 7 months
8 mgs. 8 mgs.
9 months
4 8 4 8 4 8
6 months
11 months
mgs. mgs. mgs. mgs. mgs. mgs.
2 2 3 6 1 2
years weeks weeks months year years
4 months 2% years
-
4 days
Seven patients exhibited a beneficial response to naloxone with duration Six patients of effect varying from four days to two and a half years. failed to respond to a maximum dose of 8 mgs. Inthose who responded, pain and hyperpathia was completely obtunded in six patients and partially in one, this partial effect lasting four days with no response to a subsequent maximal dose, All changes in clinical state were apparent within five minutes of the completion of naloxone administration. Side Effects All patients were observed to have an increase in'heart rate of lo-40 beats/min. over resting after the administration of naloxone: The degree of tachycardia was not dose related. Three patients exhibited a rise of more than 10 mm Hg over resting systolic blood pressure with naloxone and one a fall of 20 mm Hg over resting systolic. All changes were transitory lasting no longer than five minutes after the termination of naloxone administration. Apart from changes in rate, no alterations in E.C.G. patterns were seen. Transient dizzyness was seen in two patients, unrelated to any change in blood pressure. Discussion In ischaemic disease of the central nervous system, endogenous opioids, 421
whose titre in the cerebra-spinal fluid of these patients is increased, possibly reduce cerebral blood flow by inhibition of the locus coeruleus, this latter being an important activator of cerebra-vascular tone through the release of noradrenaline (8). Naloxone could, therefore, by antagonising the opioid effect increase vessel tone and cerebral vascular perfusion pressure. This effect is apparent in patients with ischaemic limbs in whom vascular perfusion and limb temperature can be increased by the administration of naloxone. The results presented here are not isolated findings and independent studies confirm both the beneficial effect of naloxone in thalamic syndrome and this not being due to placebo effect. The speed of onset of the analgesic effect would seem to indicate a vascular phenomenon and although initial studies with naloxone did indicate some analgesic effect (9) it is doubtful that the findings of this study confirm an effect via the accepted receptor sites. Conclusion. In patients with thalamic syndrome, naloxone administered intravenously was shown to produce a lasting beneficial effect in 54% of the trial population and exhibited as deleterious side effects. References.
(1)
Le syndrome thalamique. DEJERINE J., ROUSSY G. (1906) Revue Neurologique. 14., 521-532.
(2)
AGNEW D.C., GOLDBERG V.A. (1976) A brief trial of phenytoin therapy for thalamic pain. Bulletin Los Angeles Neurological Society. 41., 9.
(3)
FADEN A.I., JACOBS T.P., HOLADAY J.W. (1981) Opiate antagonist improves neurologic recovery after spinal injury. Science. 211., 493-494.
(4)
YOUNG W., FLAMM E.S., DEMOPOULOS H.G., TOMASULA J.H., DECRESCITO V., (1981) Effect of naloxone on post traumatic ischaemia in experimental spinal contusion. Journal of Neurosurgery. 55., 209-219.
(5)
BASKIN D.S., KIECK C.F., HOSOBUCHI Y. (1982) Naloxone reversal of ischaemic neurological deficits in baboons is not mediated by systemic effects. Life Sciences. 31., 2201-2204.
(6)
BASKIN D.S., HOSOBUCHI Y. (1981) neurological deficits in man. Lancet. 2., 272-275.
(7)
CUSS F.M., COLACO C.B., BARON J.H. (1984) Cardiac arrest after reversal of effects of opiates with naloxone. British Medical Journal. 288., 363-364.
(8)
STRAHLENDORF H.K., STRAHLENDORF J.C., BARNES C.D. (1980) Endorphin mediated inhibition of locus coeruleus neurons. Brain Research. 191., 284-288.
(9)
LASAGNA L. (1965) Drug interaction in the field of analgesic drugs. Proceedings of the Royal Society of Medicine. 58., 978-985. 422
Naloxone reversal of ischaemic