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HYPOTHERMIC SUBARACHNOID IRRIGATION FOR INTRACTABLE PAIN
1133 Health and Human Development, National Institutes of Health, U.S. Department of Health, Education, and Welfare. Requests for reprints should be addressed to M. B., Clinical Research Centre, Children’s Hospital of the District of Columbia, 2125 13th Street, N.W., Washington 9, D.C., U.S.A.
5-H.T.P. is obtainable in two forms: (1) the racemic mixture of its D- and L-isomers; and (2) the more expensive physiological form of the pure L-isomer. In one investigation, approximately 8% of an infused dose of the D form of 5-H.T.P. appeared in the urine converted to 5-H.T. and 5-H.I.A.A., suggesting a definite though small path of metabolism of the D-isomer.21 Experiments with inhibition of 5-H.T.P. by tryptophan, however, suggest that the L but not the D form of 5-H.T.P. is transported by brain slices.18 Both the racemic mixture and the pure L form were tried in patients with Down’s syndrome. Though both preparations gave satisfactory clinical results in patients over 2 months of age, the L form was less satisfactory in the neonatal period, because relatively small doses produced hypertension. It is not known whether the improvement in muscular in mongol patients is due to changes in cerebral levels of 5-H.T. The amine is present in several other places in the nervous system-the spinal cord and autonomic ganglia. Although controversial, there is evidence that the interneurons of the spinal cord respond to 5-H.T.22 and an important function for the amine at the level of the autonomic ganglia is indicated from the many experiments related to the stimulation of intestinal smooth-muscle, 8 Other sites in the central and peripheral nervous systems, such as the neuromuscular junction, do not respond to 5-H.T. under normal circumstances.23
MARY BAZELON George Washington RICHMOND S. PAINE
M.D.
M.D.
Harvard
VALERIE A. COWIE M.D. Aberd., D.P.M. PATRICIA HUNT M.D.
Department of Neurology, Children’s Hospital, Washington D.C., and the M.R.C. Psychiatric Genetics Unit, Maudsley Hospital, London
Nebraska
JOHN C. HOUCK PH.D.
Western Ontario
DERSH MAHANAND B.A.
Carthage College, Illinois
tone
Laboratory experiments suggest that 5-H.T. acts to stimulate all smooth-muscle. However, they are of limited value in understanding our results, because the mongols have depressed levels of 5-H.T. which are raised into the physiological range, whereas the levels of 5-H.T. in animals are within the normal range initially, and in most experiments these levels reached extremely high nonphysiological levels. An amine that appears to expedite transmission at one dosage level may inhibit transmission at a different dosage level (as with acetylcholine at the neuromuscular junction). Thus, the finding that 5-H.T. stimulates smooth muscle in animals in high nonphysiological doses does not necessarily help in understanding the action of this amine on the striated muscles of mongols. Despite a large body of work on this subject, it is still not clear whether 5-H.T. acts as a neurotransmitter, a neuroinhibitor, or a neuroregulatory substance, or whether several of these possibilities apply at
different concentrations.
On the basis of these preliminary observations, a controlled, double-blind study of 5-H.T.P. administration in Down’s syndrome was begun early in 1967 at the
Children’s Hospital of the District of Columbia. The results of this will not be completed for several years. Until the investigation is completed, it will not be known whether the increased muscular tone is correlated in any way with higher cerebral function. At present no prognostic inferences regarding intelligence are warranted. We gratefully acknowledge the assistance of Dr. Cecil B. Jacobson and Mr. Richard Nelson in the interpretation of chromosomal karyotypes; Miss Felice Jacobson’s work in the chemical laboratory, and Dr. Irwin Kopin’s aid in the preparation of this manuscript. This study was supported by a contract (110-44) from the Mental Retardation Branch, Division of Chronic Diseases, U.S. Public Health Service, and in part by a grant (412) from the Children’s Bureau, U.S. Department of Health, Education and Welfare, and in part by a grant (HD02044) from the National Institute of Child 21. Oates, J. A., Sjoerdsma, A. Proc. Soc. exp. Biol. Med. 1961, 108, 264. 22. Weight, F. F., Salmoiraghi, G. C. J. Pharmac. exp. Ther. 1966, 153, 420. 23. Schopp, R. T., Walsh, R. R., Rife, E. M. Archs int. Pharmacodyn. 1966,
162, 265.
HYPOTHERMIC SUBARACHNOID IRRIGATION FOR INTRACTABLE PAIN Twelve cases of intractable pain due to various lesions at different levels of the body have been treated by hypothermic subarachnoid irrigation. Worth-while relief has been obtained in seven patients, in five patients the effect was transient or unsuccessful. It is suggested that the unmyelinated C fibres are particularly susceptible to the permanent effects of cooling. No demonstrable sensory deficits and no bladder complications have been noted. Summary
INTRODUCTION
SURGICAL methods for the relief of intractable pain have been developed because analgesics produce only intermittent relief, are often used at high dosages, and are frequently accompanied by undesirable side-effects, whilst hypnotics cause somnolence and confusion. Unfortunately, surgery is often accompanied by high morbidity and mortality whilst many patients with terminal malignancy are denied surgery because of their poor general condition. The use of subarachnoid phenol with glycerin1 (added to control sp. gr.) made available some measure of pain relief for those unsuitable for surgery. The method is not always successful although worth-while relief is obtained in about 67% of casesand because of the danger of cord damage the method has been restricted to relieving pain in the lower half of the body. Wilkinson et awl. report the onset of quadriplegia after cisternal phenol injection to relieve cervical-root irritation in one
patient.
based on the idea of differentissue to hypothermia. von Euler,3 describing the stimulative effects of local cooling of nerve-fibres, commented that y and C fibres were not " excited " by cooling which stimulated thick myelinated afferent and efferent fibres. Hypothermic subarachnoid irrigation is simple, uncomplicated, and produced an encouraging degree of successful pain relief. TECHNIQUE The patient is placed on a tilting table or bed in the lateral position with the affected side beneath. Lumbar puncture is
The present method tial susceptibility of
1. 2. 3.
was
nervous
Maher, R. M. Lancet, 1955, i, 18. Wilkinson, H. A., Mark, V. H., White, J. C. J. chron. Dis. 1964, 17, 1055 von Euler, C. Acta physiol. scand. 1947, 14, suppl. no. 45.
1134 at the usual level and cerebrospinal fluid is withdrawn until subatmospheric pressures have been produced. The bed is then tilted until the affected part is below the level of lumbar puncture and 10 ml. of physiological saline solution at 2-4°C is rapidly injected. (The saline solution is frozen by placing a bottle in the freezing compartment of an ordinary refrigerator until ice crystals form.) Patients may complain of disagreeable parxsthesize in the sacral dermatomes which may last for half to one hour. Pain is completely relieved within seconds. Transient mild confusion has been noted occasionally and transient slight nystagmus was seen in one patient. Another patient had a transient severe vertigo, rotatory nystagmus, hyperventilation, sweating, and peripheral circulatory constriction after an injection to relieve shoulder
performed
pain. If one injection is unsuccessful it may be 60 ml. has been injected on one occasion.
repeated
and up
to
CASE-REPORTS
Pain in Upper Body Case 1.-Man, aged 72, a terminal case of right Pancoast tumour with evidence of spinal-cord involvement. Severe mental confusion; intractable pain in right arm with no movement possible without severe pain; pain in left arm also but less severe. Jan. 11, 1967: 40 ml. intrathecal Ringers solution at 2°C, complete relief of pain in right arm with pain-free movement. Jan: 13: 80 ml. intrathecal physiological solution (0-9%saline) at 2°C, complete relief of left arm pain. No further analgesics required. Died Jan. 27. Case 2.-Man, aged 67. Malignant right supraclavicular lymph-nodes. Severe pain right supraclavicular region radiating down the right arm for 2 months. Analgesics relieved pain for a few hours only. Arm movement restricted because of pain. Evidence of spinal-cord involvement with left lower limb clonus and increased reflexes with extensor plantar response. Hyperpathia in right arm. Jan. 17, 1967: 10 ml. of intrathecal 0-9% saline at 2°C, complete pain relief within seconds. No hyperpathia. Analgesics discontinued. Able to use arm normally. Radiotherapy was given for the right nodes which gradually diminished in size over supraclavicular the succeeding months. He remained completely free of pain up until the last follow-up on April 13 when there was still some induration in the right supraclavicular fossa. -
Case 3.-Man, aged 56. Left Pancoast tumour. Severe shoulder and arm and interscapular region. rest with vital capacity of 0.8 litre. Considered unsafe for high cervical cordotomy. Full radiotherapy, Dec. 1, 1966, but pain continued with increasing severity. Difficult to dress because of pain and movement of arm intensely painful. Jan. 26, 1967: 20 ml. of intrathecal 0-9%, saline at 2"C. Complete relief of pain after 1 minute and able to move arm normally without pain. Analgesics discontinued and remained pain-free until death on March 19.
pain in left Dyspnoeic at
Case 4.-Man, aged 65. Metastatic teratoma of left humerus. 10 months discomfort in left shoulder becoming increasingly severe over the past 4 months with evidence of invasion of radial nerve. Left shoulder girdle grossly deformed by growth. Extremely painful to direct pressure and pain in shoulder girdle, arm and hand with painful paraesthesiae and hyperpathia right thumb, index, and forearm. Insomniac, apprehensive, and agitated. Pain intermittently relieved with 50 mg. of pethidine 4-hourly but complained of severe confusion and sleepiness. Feb. 25, 1967: 40 ml. intrathecal 0-9% saline at 3°C. Complete relief of all pain after 1 minute. No pain on pressure. No further analgesics given. Over the next few days he complained of occasional discomfort which disappeared within minutes of taking placebo tablets (nicotinic acid). Although still agitated and apprehensive he required only evening sedation. The limb was still painless to deep pressure and he started a course of cyclophosphamide which was severe over the past 4 months with evidence of invasion of discontinued because of a low blood-count. Pain recurred middle of April, requiring analgesics. May 5: 40 ml. intrathe-
0-9% saline at 3°C produced severe confusion for several hours, but pain was relieved. Case 5.-Woman, aged 39. Recurrence in left chest wall cal
after left pneumonectomy for bronchial carcinoma.
Severe
pain left shoulder and inner aspect of left arm with pain due to local involvement of left breast-worse during periods. The pain kept her awake at night and was only partly controlled by analgesics. She had considerable pain on local pressure over the growth. Feb. 22, 1967: 20 ml. intrathecal 0-9% saline at 2°C. Complete relief of pain within 1 minute which lasted for 8 hours, she then developed slight intermittent pain in the left shoulder which had returned to its previous severity by Feb. 28. March 1: 60 ml. intrathecal 0-9% saline at 2°C produced complete relief of pain within 1 minute although a little pain returned within 12 hours. She was finally admitted for cytotoxic therapy but her medical attendants noted that the pain was now less troublesome and she appeared more disturbed over the swelling rather than the pain. Case 6.-Man, aged 71. A terminal case of left Pancoast tumour with severe pain in left shoulder and in a pathological fracture of the upper third of the humerus. Confused. March 22, 1967: 20 ml. intrathecal 0-9% saline at 2°C. Complete relief within seconds lasting for 2-3 hours. Pain at the fracture site then returned but the shoulder pain which had been present before the pathological fracture was completely relieved. March 27: 40 ml. intrathecal 0-9% saline at 2°C. Notable relief of local tenderness at fracture site but accompanied by severe vertigo, nystagmus, hyperventilation, and peripheral circulatory stasis lasting a few minutes. He remained pain-free apart from local discomfort at the fracture site but nursing care was greatly facilitated and he did not again complain of the shoulder pain. Died April 25. Pain in Lower Body Case 7.-Woman, aged 73. Pelvic invasion from bladder carcinoma with right-iliac-vein thrombosis. Severe pain right sciatic distribution. Heavy doses analgesics and hypnotics for several months. Hyperpathia right L5 dermatome with weakness of right ankle dorsiflexion. Feb. 7, 1967: 20 ml. intrathecal 0-9% saline at 2°C produced complete relief of pain and hyperpathia but within 30 minutes she complained of very painful parxsthesix in the sacral dermatomes. She continued to demand hypnotics which were continued but slept better at night than previously. General improvement was evident for at least 10 days and analgesic dosage now seemed adequate. Case 8.-Man, aged 59. Retroperitoneal sarcoma with invasion of ilium and iliac fossa. Severe pain left hip both to direct pressure and on movement of left knee and hip joint which were fixed in flexion. Any attempt at straightening the left knee provoked severe pain in the left hip. Analgesics only partially successful in relieving pain. March 21, 1967: 20 ml. intrathecal 0-9% saline at 2OC. Complete pain-relief after No tenderness on pressure. Leg could be a few seconds. extended painlessly as far as contracture allowed. No further analgesics necessary-sleeping well. Leg gradually extended until straight, facilitating nursing. He was sufficiently relieved to be able to sleep on the left side and all analgesics were discontinued. He died on April 4. Case 9.-Woman, aged 75. Carcinoma of breast with spinal metastasis, severe pain lumbar spine radiating around the waist and up into cervical region. All movement painful, walking agonising. March 29, 1967: 10 ml. 0-9%, saline at 3°C intrathecally. Immediate relief of pain. Able to get off bed and walk back to trolley pain-free. This old lady had been a keen competition ballroom dancer and on April 2 she danced the Boston twostep with her medical attendant and continued pain free. No analgesics were given until April 29 when pain recurred accompanied by general deterioration. Pain Due to Central-nervous-system Lesions The next three cases are examples of pain due to centralnervous-system lesions and a hypothermic subarachnoid irrigation failed to procure worth-while relief. Case 10.-Woman, aged 61. Intractable pain between the
1135
shoulder blades going round both sides of the back but mostly the left side sometimes associated with pain on the left lower abdomen. Kyphoscoliosis at D 8 and 9, myelography normal. Analgesics had failed to relieve her pain and she started taking pethidine. Left dorsal rhizotomy D 6-9 inclusive on May 25, 1966, failed to relieve her pain which was still present but now in the anxsthetic zone. Intrathecal injection of 0’9% saline at 5°C given on Nov. 2 produced transient to
improvement in the pain experienced in the anxsthetic
zone
but pain in the hypersesthetic zone between the rhizotomy and normal skin remained unchanged. On Nov. 9 a right high cervical anterolateral cordotomy was performed with a good level of analgesia but she returned later with recurrence of pain. Case 11.-A woman, aged 77. Arteriosclerotic spinal-cord infarction. Severe right trunk and left leg pain. Hyperpathia left thigh. Jan. 26, 1967: 20 ml. intrathecal 0-9% saline at 2°C. No relief. Feb. 24: rhizotomy right D 6-9 posterior roots
without pain relief. Electrolytic lesion Lissauer tract and substantia gelatinosa eliminated right trunk pain. Preliminary histological examination shows fine widespread vacuolation and pallor of myelin staining but further examination is proceeding. Case 12.-Woman, aged 43. Multiple sclerosis with lower limb spasticity. Severe pain buttocks and "front passage". Carried a cushion everywhere because of pain on sitting. Hyperassthesia sacral dermatomes. March 21, 1967: 20 ml. intrathecal 0-9% saline at 2°C. No relief of pain. She was able to walk with greater ease and sit without discomfort now, however, although she complained that the buttocks and legs felt "soft". Examination revealed considerable decrease of lower limb spasticity and she is now able to tolerate stroking of the sacral dermatomes or direct pressure. In addition she has now given up the use of the cushion but although the hyperxsthesia had disappeared she still suffered constant pain. DISCUSSION
As far as I know, hypothermic spinal-cord irrigation has not previously been used for the relief of pain. Negrin4 used hypothermic irrigation for spasticity and to protect the cord against the effects of trauma. His method requires the insertion of catheters into the epidural space or into the subarachnoid space after laminectomy and under general anxsthesia. Irrigation is prolonged and usually requires a specially developed perfusion machine. The temperatures used for the treatment of spasticity have not been as low as those used by me. The cases treated so far have been unselected, but success seems most likely in patients where posterior rhizotomy might be expected to be successful. It is unlikely to help patients with pain due to central-nervoussystem disease or pain of such duration that it has become established centrally (cases 10-12). In nine of the twelve cases pain relief was immediate although in two of these the relief was only transient, lasting for a few days. An important feature has been the relief of pain without producing any demonstrable sensory deficits. Presumably, unmyelinated C fibres are more susceptible to cooling than thickly myelinated fibres which may indeed be stimulated, as suggested by von Euler.3 This is supported by the findings in many patients of relief of pain but distasteful although fortunately transient paraesthesiae in the sacral dermatomes. Pain loss without sensory deficit has been reported for phenolalthough most
commonly pain relief is not accomplished without sensory deficit. In this series, however, pain relief was never accompanied by any demonstrable sensory loss, despite careful and repeated testing. The physiopathology of this effect is being further investigated but the production of 4. 5.
Negrin, J. Excerpta med. int. Congr. Ser. 1966, 110. Stewart, W. A., Lourie, H. J. Neurosurg. 1963, 20,
64.
pain relief without influencing other modalities of sensation such as distinction between sharp and blunt suggests that the effect of hypothermia may be upon neuronal circuits set up by peripheral conductive pathways such as thinly medullated or unmedullated nerve fibres. It should be appreciated that patients with upperextremity pain impose a severe test on the efficacy of the method and the procedure should be more effective with lower-extremity pain. It has been assumed that saline solution at 2-4°C is hyperbaric with respect to cerebrospinal fluid but an attempt has been made to empty the spinal subarachnoid space of cerebrospinal fluid and to reach the roots by rapid injection. Possibly, cisternal puncture and irrigation would be more successful for upper-limb pain, but because of the unpleasant sideeffects experienced in injection this procedure may prove hazardous and the aim has been to develop a safe and simple procedure. Direct, local cooling of posterior roots should be even more effective but has the disadvantage of requiring laminectomy. The absence of bladder complications and sensory deficits gives this method advantages over phenol and, most importantly, upper-extremity pain can be relieved easily and safely. The duration of pain relief is variable but it is unlikely to be as permanent as that produced by rhizotomy. In the treatment of malignant disease, however, even short-term relief is worth while, whilst the relative simplicity of the procedure commends it for terminal cases where extensive procedures are not indicated. I thank the neuropathologists of the neuropathological laboratory for preliminary histological examination in case 11. Department of Surgical Neurology, Royal Infirmary, Edinburgh 3
EDWARD HITCHCOCK M.B. Birm., F.R.C.S.
RECEPTOR MECHANISMS IN THE HYPERGLYCÆMIC RESPONSE TO ADRENALINE IN MAN The hyperglycæmic response to adrenaline in man was abolished by blocking both &agr; and &bgr; receptors with phentolamine and propranolol. The rise of glucose was not prevented by either blocking agent alone, but &bgr;-receptor blockade abolished the rise of lactate. This suggests that the &bgr; receptors are situated in muscle and implies that &agr; receptors are in liver. Confirmation for this comes from subjects with dietary ketosis in whom liver glycolysis is in abeyance, when &bgr;-receptor blockade abolishes the rise of glucose as well as of lactate. Summary
INTRODUCTION
THE receptors responsible for the rise in the concentration of blood-glucose caused by adrenaline in animals or in man have not been defined.! It has been suggested from indirect evidence in rats2 that two separate mechanisms may contribute to the hyperglycaemic effect of catecholamines. One involves glycogenolysis in the liver and is probably mediated by CI. receptors; the other involves glycogenolysis in muscle producing lactic acid which is subsequently converted in the liver to glucose (the peripheral release of lactic acid seems to be mediated Hagen, J. H., Hagen, P. B. in Actions of Hormones on Molecular Processes (edited by G. Litwach and D. Kritchevsky); p. 271. New York, 1964. 2. Fleming, W. W., Kenny, A. D. Br. J. Pharmac. 1964. 22. 267. 1.
5-H.T.P. is obtainable in two forms: (1) the racemic mixture of its D- and L-isomers; and (2) the more expensive physiological form of the pure L-isomer. In one investigation, approximately 8% of an infused dose of the D form of 5-H.T.P. appeared in the urine converted to 5-H.T. and 5-H.I.A.A., suggesting a definite though small path of metabolism of the D-isomer.21 Experiments with inhibition of 5-H.T.P. by tryptophan, however, suggest that the L but not the D form of 5-H.T.P. is transported by brain slices.18 Both the racemic mixture and the pure L form were tried in patients with Down’s syndrome. Though both preparations gave satisfactory clinical results in patients over 2 months of age, the L form was less satisfactory in the neonatal period, because relatively small doses produced hypertension. It is not known whether the improvement in muscular in mongol patients is due to changes in cerebral levels of 5-H.T. The amine is present in several other places in the nervous system-the spinal cord and autonomic ganglia. Although controversial, there is evidence that the interneurons of the spinal cord respond to 5-H.T.22 and an important function for the amine at the level of the autonomic ganglia is indicated from the many experiments related to the stimulation of intestinal smooth-muscle, 8 Other sites in the central and peripheral nervous systems, such as the neuromuscular junction, do not respond to 5-H.T. under normal circumstances.23
MARY BAZELON George Washington RICHMOND S. PAINE
M.D.
M.D.
Harvard
VALERIE A. COWIE M.D. Aberd., D.P.M. PATRICIA HUNT M.D.
Department of Neurology, Children’s Hospital, Washington D.C., and the M.R.C. Psychiatric Genetics Unit, Maudsley Hospital, London
Nebraska
JOHN C. HOUCK PH.D.
Western Ontario
DERSH MAHANAND B.A.
Carthage College, Illinois
tone
Laboratory experiments suggest that 5-H.T. acts to stimulate all smooth-muscle. However, they are of limited value in understanding our results, because the mongols have depressed levels of 5-H.T. which are raised into the physiological range, whereas the levels of 5-H.T. in animals are within the normal range initially, and in most experiments these levels reached extremely high nonphysiological levels. An amine that appears to expedite transmission at one dosage level may inhibit transmission at a different dosage level (as with acetylcholine at the neuromuscular junction). Thus, the finding that 5-H.T. stimulates smooth muscle in animals in high nonphysiological doses does not necessarily help in understanding the action of this amine on the striated muscles of mongols. Despite a large body of work on this subject, it is still not clear whether 5-H.T. acts as a neurotransmitter, a neuroinhibitor, or a neuroregulatory substance, or whether several of these possibilities apply at
different concentrations.
On the basis of these preliminary observations, a controlled, double-blind study of 5-H.T.P. administration in Down’s syndrome was begun early in 1967 at the
Children’s Hospital of the District of Columbia. The results of this will not be completed for several years. Until the investigation is completed, it will not be known whether the increased muscular tone is correlated in any way with higher cerebral function. At present no prognostic inferences regarding intelligence are warranted. We gratefully acknowledge the assistance of Dr. Cecil B. Jacobson and Mr. Richard Nelson in the interpretation of chromosomal karyotypes; Miss Felice Jacobson’s work in the chemical laboratory, and Dr. Irwin Kopin’s aid in the preparation of this manuscript. This study was supported by a contract (110-44) from the Mental Retardation Branch, Division of Chronic Diseases, U.S. Public Health Service, and in part by a grant (412) from the Children’s Bureau, U.S. Department of Health, Education and Welfare, and in part by a grant (HD02044) from the National Institute of Child 21. Oates, J. A., Sjoerdsma, A. Proc. Soc. exp. Biol. Med. 1961, 108, 264. 22. Weight, F. F., Salmoiraghi, G. C. J. Pharmac. exp. Ther. 1966, 153, 420. 23. Schopp, R. T., Walsh, R. R., Rife, E. M. Archs int. Pharmacodyn. 1966,
162, 265.
HYPOTHERMIC SUBARACHNOID IRRIGATION FOR INTRACTABLE PAIN Twelve cases of intractable pain due to various lesions at different levels of the body have been treated by hypothermic subarachnoid irrigation. Worth-while relief has been obtained in seven patients, in five patients the effect was transient or unsuccessful. It is suggested that the unmyelinated C fibres are particularly susceptible to the permanent effects of cooling. No demonstrable sensory deficits and no bladder complications have been noted. Summary
INTRODUCTION
SURGICAL methods for the relief of intractable pain have been developed because analgesics produce only intermittent relief, are often used at high dosages, and are frequently accompanied by undesirable side-effects, whilst hypnotics cause somnolence and confusion. Unfortunately, surgery is often accompanied by high morbidity and mortality whilst many patients with terminal malignancy are denied surgery because of their poor general condition. The use of subarachnoid phenol with glycerin1 (added to control sp. gr.) made available some measure of pain relief for those unsuitable for surgery. The method is not always successful although worth-while relief is obtained in about 67% of casesand because of the danger of cord damage the method has been restricted to relieving pain in the lower half of the body. Wilkinson et awl. report the onset of quadriplegia after cisternal phenol injection to relieve cervical-root irritation in one
patient.
based on the idea of differentissue to hypothermia. von Euler,3 describing the stimulative effects of local cooling of nerve-fibres, commented that y and C fibres were not " excited " by cooling which stimulated thick myelinated afferent and efferent fibres. Hypothermic subarachnoid irrigation is simple, uncomplicated, and produced an encouraging degree of successful pain relief. TECHNIQUE The patient is placed on a tilting table or bed in the lateral position with the affected side beneath. Lumbar puncture is
The present method tial susceptibility of
1. 2. 3.
was
nervous
Maher, R. M. Lancet, 1955, i, 18. Wilkinson, H. A., Mark, V. H., White, J. C. J. chron. Dis. 1964, 17, 1055 von Euler, C. Acta physiol. scand. 1947, 14, suppl. no. 45.
1134 at the usual level and cerebrospinal fluid is withdrawn until subatmospheric pressures have been produced. The bed is then tilted until the affected part is below the level of lumbar puncture and 10 ml. of physiological saline solution at 2-4°C is rapidly injected. (The saline solution is frozen by placing a bottle in the freezing compartment of an ordinary refrigerator until ice crystals form.) Patients may complain of disagreeable parxsthesize in the sacral dermatomes which may last for half to one hour. Pain is completely relieved within seconds. Transient mild confusion has been noted occasionally and transient slight nystagmus was seen in one patient. Another patient had a transient severe vertigo, rotatory nystagmus, hyperventilation, sweating, and peripheral circulatory constriction after an injection to relieve shoulder
performed
pain. If one injection is unsuccessful it may be 60 ml. has been injected on one occasion.
repeated
and up
to
CASE-REPORTS
Pain in Upper Body Case 1.-Man, aged 72, a terminal case of right Pancoast tumour with evidence of spinal-cord involvement. Severe mental confusion; intractable pain in right arm with no movement possible without severe pain; pain in left arm also but less severe. Jan. 11, 1967: 40 ml. intrathecal Ringers solution at 2°C, complete relief of pain in right arm with pain-free movement. Jan: 13: 80 ml. intrathecal physiological solution (0-9%saline) at 2°C, complete relief of left arm pain. No further analgesics required. Died Jan. 27. Case 2.-Man, aged 67. Malignant right supraclavicular lymph-nodes. Severe pain right supraclavicular region radiating down the right arm for 2 months. Analgesics relieved pain for a few hours only. Arm movement restricted because of pain. Evidence of spinal-cord involvement with left lower limb clonus and increased reflexes with extensor plantar response. Hyperpathia in right arm. Jan. 17, 1967: 10 ml. of intrathecal 0-9% saline at 2°C, complete pain relief within seconds. No hyperpathia. Analgesics discontinued. Able to use arm normally. Radiotherapy was given for the right nodes which gradually diminished in size over supraclavicular the succeeding months. He remained completely free of pain up until the last follow-up on April 13 when there was still some induration in the right supraclavicular fossa. -
Case 3.-Man, aged 56. Left Pancoast tumour. Severe shoulder and arm and interscapular region. rest with vital capacity of 0.8 litre. Considered unsafe for high cervical cordotomy. Full radiotherapy, Dec. 1, 1966, but pain continued with increasing severity. Difficult to dress because of pain and movement of arm intensely painful. Jan. 26, 1967: 20 ml. of intrathecal 0-9%, saline at 2"C. Complete relief of pain after 1 minute and able to move arm normally without pain. Analgesics discontinued and remained pain-free until death on March 19.
pain in left Dyspnoeic at
Case 4.-Man, aged 65. Metastatic teratoma of left humerus. 10 months discomfort in left shoulder becoming increasingly severe over the past 4 months with evidence of invasion of radial nerve. Left shoulder girdle grossly deformed by growth. Extremely painful to direct pressure and pain in shoulder girdle, arm and hand with painful paraesthesiae and hyperpathia right thumb, index, and forearm. Insomniac, apprehensive, and agitated. Pain intermittently relieved with 50 mg. of pethidine 4-hourly but complained of severe confusion and sleepiness. Feb. 25, 1967: 40 ml. intrathecal 0-9% saline at 3°C. Complete relief of all pain after 1 minute. No pain on pressure. No further analgesics given. Over the next few days he complained of occasional discomfort which disappeared within minutes of taking placebo tablets (nicotinic acid). Although still agitated and apprehensive he required only evening sedation. The limb was still painless to deep pressure and he started a course of cyclophosphamide which was severe over the past 4 months with evidence of invasion of discontinued because of a low blood-count. Pain recurred middle of April, requiring analgesics. May 5: 40 ml. intrathe-
0-9% saline at 3°C produced severe confusion for several hours, but pain was relieved. Case 5.-Woman, aged 39. Recurrence in left chest wall cal
after left pneumonectomy for bronchial carcinoma.
Severe
pain left shoulder and inner aspect of left arm with pain due to local involvement of left breast-worse during periods. The pain kept her awake at night and was only partly controlled by analgesics. She had considerable pain on local pressure over the growth. Feb. 22, 1967: 20 ml. intrathecal 0-9% saline at 2°C. Complete relief of pain within 1 minute which lasted for 8 hours, she then developed slight intermittent pain in the left shoulder which had returned to its previous severity by Feb. 28. March 1: 60 ml. intrathecal 0-9% saline at 2°C produced complete relief of pain within 1 minute although a little pain returned within 12 hours. She was finally admitted for cytotoxic therapy but her medical attendants noted that the pain was now less troublesome and she appeared more disturbed over the swelling rather than the pain. Case 6.-Man, aged 71. A terminal case of left Pancoast tumour with severe pain in left shoulder and in a pathological fracture of the upper third of the humerus. Confused. March 22, 1967: 20 ml. intrathecal 0-9% saline at 2°C. Complete relief within seconds lasting for 2-3 hours. Pain at the fracture site then returned but the shoulder pain which had been present before the pathological fracture was completely relieved. March 27: 40 ml. intrathecal 0-9% saline at 2°C. Notable relief of local tenderness at fracture site but accompanied by severe vertigo, nystagmus, hyperventilation, and peripheral circulatory stasis lasting a few minutes. He remained pain-free apart from local discomfort at the fracture site but nursing care was greatly facilitated and he did not again complain of the shoulder pain. Died April 25. Pain in Lower Body Case 7.-Woman, aged 73. Pelvic invasion from bladder carcinoma with right-iliac-vein thrombosis. Severe pain right sciatic distribution. Heavy doses analgesics and hypnotics for several months. Hyperpathia right L5 dermatome with weakness of right ankle dorsiflexion. Feb. 7, 1967: 20 ml. intrathecal 0-9% saline at 2°C produced complete relief of pain and hyperpathia but within 30 minutes she complained of very painful parxsthesix in the sacral dermatomes. She continued to demand hypnotics which were continued but slept better at night than previously. General improvement was evident for at least 10 days and analgesic dosage now seemed adequate. Case 8.-Man, aged 59. Retroperitoneal sarcoma with invasion of ilium and iliac fossa. Severe pain left hip both to direct pressure and on movement of left knee and hip joint which were fixed in flexion. Any attempt at straightening the left knee provoked severe pain in the left hip. Analgesics only partially successful in relieving pain. March 21, 1967: 20 ml. intrathecal 0-9% saline at 2OC. Complete pain-relief after No tenderness on pressure. Leg could be a few seconds. extended painlessly as far as contracture allowed. No further analgesics necessary-sleeping well. Leg gradually extended until straight, facilitating nursing. He was sufficiently relieved to be able to sleep on the left side and all analgesics were discontinued. He died on April 4. Case 9.-Woman, aged 75. Carcinoma of breast with spinal metastasis, severe pain lumbar spine radiating around the waist and up into cervical region. All movement painful, walking agonising. March 29, 1967: 10 ml. 0-9%, saline at 3°C intrathecally. Immediate relief of pain. Able to get off bed and walk back to trolley pain-free. This old lady had been a keen competition ballroom dancer and on April 2 she danced the Boston twostep with her medical attendant and continued pain free. No analgesics were given until April 29 when pain recurred accompanied by general deterioration. Pain Due to Central-nervous-system Lesions The next three cases are examples of pain due to centralnervous-system lesions and a hypothermic subarachnoid irrigation failed to procure worth-while relief. Case 10.-Woman, aged 61. Intractable pain between the
1135
shoulder blades going round both sides of the back but mostly the left side sometimes associated with pain on the left lower abdomen. Kyphoscoliosis at D 8 and 9, myelography normal. Analgesics had failed to relieve her pain and she started taking pethidine. Left dorsal rhizotomy D 6-9 inclusive on May 25, 1966, failed to relieve her pain which was still present but now in the anxsthetic zone. Intrathecal injection of 0’9% saline at 5°C given on Nov. 2 produced transient to
improvement in the pain experienced in the anxsthetic
zone
but pain in the hypersesthetic zone between the rhizotomy and normal skin remained unchanged. On Nov. 9 a right high cervical anterolateral cordotomy was performed with a good level of analgesia but she returned later with recurrence of pain. Case 11.-A woman, aged 77. Arteriosclerotic spinal-cord infarction. Severe right trunk and left leg pain. Hyperpathia left thigh. Jan. 26, 1967: 20 ml. intrathecal 0-9% saline at 2°C. No relief. Feb. 24: rhizotomy right D 6-9 posterior roots
without pain relief. Electrolytic lesion Lissauer tract and substantia gelatinosa eliminated right trunk pain. Preliminary histological examination shows fine widespread vacuolation and pallor of myelin staining but further examination is proceeding. Case 12.-Woman, aged 43. Multiple sclerosis with lower limb spasticity. Severe pain buttocks and "front passage". Carried a cushion everywhere because of pain on sitting. Hyperassthesia sacral dermatomes. March 21, 1967: 20 ml. intrathecal 0-9% saline at 2°C. No relief of pain. She was able to walk with greater ease and sit without discomfort now, however, although she complained that the buttocks and legs felt "soft". Examination revealed considerable decrease of lower limb spasticity and she is now able to tolerate stroking of the sacral dermatomes or direct pressure. In addition she has now given up the use of the cushion but although the hyperxsthesia had disappeared she still suffered constant pain. DISCUSSION
As far as I know, hypothermic spinal-cord irrigation has not previously been used for the relief of pain. Negrin4 used hypothermic irrigation for spasticity and to protect the cord against the effects of trauma. His method requires the insertion of catheters into the epidural space or into the subarachnoid space after laminectomy and under general anxsthesia. Irrigation is prolonged and usually requires a specially developed perfusion machine. The temperatures used for the treatment of spasticity have not been as low as those used by me. The cases treated so far have been unselected, but success seems most likely in patients where posterior rhizotomy might be expected to be successful. It is unlikely to help patients with pain due to central-nervoussystem disease or pain of such duration that it has become established centrally (cases 10-12). In nine of the twelve cases pain relief was immediate although in two of these the relief was only transient, lasting for a few days. An important feature has been the relief of pain without producing any demonstrable sensory deficits. Presumably, unmyelinated C fibres are more susceptible to cooling than thickly myelinated fibres which may indeed be stimulated, as suggested by von Euler.3 This is supported by the findings in many patients of relief of pain but distasteful although fortunately transient paraesthesiae in the sacral dermatomes. Pain loss without sensory deficit has been reported for phenolalthough most
commonly pain relief is not accomplished without sensory deficit. In this series, however, pain relief was never accompanied by any demonstrable sensory loss, despite careful and repeated testing. The physiopathology of this effect is being further investigated but the production of 4. 5.
Negrin, J. Excerpta med. int. Congr. Ser. 1966, 110. Stewart, W. A., Lourie, H. J. Neurosurg. 1963, 20,
64.
pain relief without influencing other modalities of sensation such as distinction between sharp and blunt suggests that the effect of hypothermia may be upon neuronal circuits set up by peripheral conductive pathways such as thinly medullated or unmedullated nerve fibres. It should be appreciated that patients with upperextremity pain impose a severe test on the efficacy of the method and the procedure should be more effective with lower-extremity pain. It has been assumed that saline solution at 2-4°C is hyperbaric with respect to cerebrospinal fluid but an attempt has been made to empty the spinal subarachnoid space of cerebrospinal fluid and to reach the roots by rapid injection. Possibly, cisternal puncture and irrigation would be more successful for upper-limb pain, but because of the unpleasant sideeffects experienced in injection this procedure may prove hazardous and the aim has been to develop a safe and simple procedure. Direct, local cooling of posterior roots should be even more effective but has the disadvantage of requiring laminectomy. The absence of bladder complications and sensory deficits gives this method advantages over phenol and, most importantly, upper-extremity pain can be relieved easily and safely. The duration of pain relief is variable but it is unlikely to be as permanent as that produced by rhizotomy. In the treatment of malignant disease, however, even short-term relief is worth while, whilst the relative simplicity of the procedure commends it for terminal cases where extensive procedures are not indicated. I thank the neuropathologists of the neuropathological laboratory for preliminary histological examination in case 11. Department of Surgical Neurology, Royal Infirmary, Edinburgh 3
EDWARD HITCHCOCK M.B. Birm., F.R.C.S.
RECEPTOR MECHANISMS IN THE HYPERGLYCÆMIC RESPONSE TO ADRENALINE IN MAN The hyperglycæmic response to adrenaline in man was abolished by blocking both &agr; and &bgr; receptors with phentolamine and propranolol. The rise of glucose was not prevented by either blocking agent alone, but &bgr;-receptor blockade abolished the rise of lactate. This suggests that the &bgr; receptors are situated in muscle and implies that &agr; receptors are in liver. Confirmation for this comes from subjects with dietary ketosis in whom liver glycolysis is in abeyance, when &bgr;-receptor blockade abolishes the rise of glucose as well as of lactate. Summary
INTRODUCTION
THE receptors responsible for the rise in the concentration of blood-glucose caused by adrenaline in animals or in man have not been defined.! It has been suggested from indirect evidence in rats2 that two separate mechanisms may contribute to the hyperglycaemic effect of catecholamines. One involves glycogenolysis in the liver and is probably mediated by CI. receptors; the other involves glycogenolysis in muscle producing lactic acid which is subsequently converted in the liver to glucose (the peripheral release of lactic acid seems to be mediated Hagen, J. H., Hagen, P. B. in Actions of Hormones on Molecular Processes (edited by G. Litwach and D. Kritchevsky); p. 271. New York, 1964. 2. Fleming, W. W., Kenny, A. D. Br. J. Pharmac. 1964. 22. 267. 1.