LOFEXIDINE, A CLONIDINE ANALOGUE EFFECTIVE IN OPIATE WITHDRAWAL

991

Letters

to

the Editor

THE CRISIS FOR POSTGRADUATE MEDICINE

SiR,-The crisis facing the postgraduate institutes of the British Postgraduate Medical Federation is financial: it is very grave, threatening not simply some of their activities but also their continued existence in anything resembling their present form, and appears to have resulted as a largely accidental byproduct of the Government’s policy on overseas students. The constitutional position of the institutes, called into question by the Flowers report, has in effect been shelved pending the resolution of the financial problem. There is, however, general acceptance of the proposition that the Cardiothoracic Institute and the Institutes of Cancer Research, Child Health, Neurology, Ophthalmology, and Psychiatry should retain their present degree of autonomy and with it the London Advisory Group has recommended that a board of governors should continue to administer the associated hospitals - the Brompton, Royal Marsden, Great Ormond Street, the National, Moorfields, and Maudsley. The Institutes of Dermatology and Urology, whose associated hospitals are in urgent need of rehousing, are likely to become closely associated with general medical schools in the next two or three years. The Institutes of Orthopaedics and of Laryngology and Otology, where only partial relocation is required, are in negotiation with the University College/Middlesex complex. The Institute of Obstetrics and Gynaecology will probably remain at Queen Charlotte’s but become more closely linked to the Royal Postgraduate Medical School. The Institute of Dental Surgery is likely to remain in situ and independent for some years yet. No decision has been reached on the future of the Institute of Basic Medical Sciences, though many around the University believe that the University Grants Committee grant will be phased out completely even though the Royal College of Surgeons, an equal copartner in this enterprise, has no resources capable of sustaining the whole of the Institute as now constituted. However, the big query is not over constitution but over finance. The effects of the overseas student fee. policy, as implemented by the University Grants Committee and the University of London, were always recognised to be potentially disastrous for the postgraduate institutes, as for the Royal Postgraduate Medical School and London School of Hygiene and Tropical Medicine, but, despite numerous representations, the cause of the impending catastrophe has seldom been appreciated outside the schools involved. The calculation of the loss of grant income stems from the basic premise that the grant should be adjusted to whole-time student numbers and that all activities of university institutions can be related to this basic teaching activity. In the case of postgraduate medicine, much of the teaching is on a part-time or short course basis-that is, the requirement of doctors in practice and employment-and a high proportion of the work is research, unrelated to student partici-

pation. The overseas student fee policy simply takes the total cost of the school divided by the number of students as the unit cost and subtracts from the recurrent grant that unit multiplied by the proportion from overseas in the total student body at the end of December, 1978. Since the British Postgraduate Medical Federation had at that time 44% of whole-time students from abroad, it faces the loss, over three years, of 44% of its grant income, or, at present, more than10 000 for every student. The fee charged this year was ,65000, when it could be obtained, but since very many of the students working for higher degrees are on the salaried staff, and not at all in the same position as undergraduate students, this fee must often be waived. The gap between the cut in recurrent grant and the fee income is therefore enormous. Student numbers in this year have been well maintained, because overseas authorities had little time in which to redirect them, but next year, when the mimmum fee will be 6000 and various countries have already made other arrangements, numbers are likely to drop considerably. The effective loss of recurrent income in real terms during the present year has been of the order of 17% and this is only the first of

three phases of the cuts. By freezing posts, by mobilising reserves, and by the use of some non-recurrent grants, the Federation hopes to maintain all institutes in balance during this year: but a second cut on the same basis could not be sustained. Savings can now only be made on salary expenditure and a reduction of staffng levels is therefore inevitable. The difficulty lies in effecting such a policy. Professors, readers, and some senior lecturers have a considerable, though so far untested, security of tenure until retiring age, and a simple imposition of redundancy could render an institute liable to action for unfair dismissal and a crippling financial penalty. Premature retirement schemes are available and offer advantageous terms for the teacher, but not everyone wants to retire early, and in any case the expense to the employer is considerable. Redundancy for non-academic staff is possible, probably unavoidable, but is certainly disagreeable and not without financial repercussions. A large part of the non-recurrent grant available this year is being directed towards severance pay, but can hardly achieve the degree of reduction required to meet the expected deficit in the next year. Moreover, the clinical involvement of academic and technical staffin the work of the associated hospital is such that their withdrawal could have a crippling effect on the clinical service and on the higher specialist training programmes. Certain departments simply cannot be closed if the institute is to stay in business at all. A relentless pursuit of present government policy and its arithmetical implementation by the University Grants Committee could well bring some institutes to bankruptcy and those most at risk are naturally those with most commitments, in fact the largest and most

prestigious. It seems incredible that the Government should wish to sacrifice the national assets which these institutes represent, simply because they wish to make overseas students contribute rather more: but unless there is some change of direction that sacrifice could well be the result. Its avoidance requires some rethinking, in both the Department of Education and Science and in the Department of Health and Social Security, since the financial responsibility for the academic aspects of postgraduate medical education has never been fairly apportioned between the two Departments. Central Office, British Postgraduate Medical Federation, 33 Millman Street, London WC1N 3EJ

D. INNES WILLIAMS, Director

LOFEXIDINE, A CLONIDINE ANALOGUE EFFECTIVE IN OPIATE WITHDRAWAL

SIR,-We have found clonidine to be useful in easing the pain and discomfort of opiate withdrawal in outpatients attempting to detoxify from heroin or methadone.I-3 Our studies and those of Gold et a1.4 indicate that clonidine might best be used as a nonopiate anti-withdrawal treatment during the 1-2 week transition period between discontinuation of opiates and induction onto the opiate antagonist, naltrexone.5 However, clonidine’s potent sedative and hypotensive effects might limit its clinical usefulness, especially in outpatients.2,3 Drowsiness and dizziness induced by clonidine can interfere with normal daily activities and thereby pose a significant obstacle for some patients who might be well-suited for clonidine treatment-namely, those in employment who need to continue working while trying to detoxify from opiates. A nonopiate anti-withdrawal agent with greater specificity than clonidine and fewer side effects might be safer and more effective for outpatient opiate detoxification. We now report preliminary findings with lofexidine (Merrell Dow Pharmaceuticals) a structural analogue of clonidine that seems 1. Washton

AM, Resnick RB, Rawson RA. Clonidine hydrochloride: a nonopiate for opiate withdrawal. Psychopharm Bull 1980; 16: 50-52. Washton AM, Reswick RB. Clonidine for outpatient opiate detoxification. Lancet treatment

2.

1980; 1: 1078-79. 3. Washton AM, Resnick RB Clondine for opiate detoxification: Outpatient clinical trials. Am J Psychiat 1980; 137: 1121-22. 4. Gold MS, Pottash AC, Sweeney DR et al. Opiate withdrawal using clonidine JAMA 1980; 243: 343-46. 5. Resnick RB, Schuyten-Resnick E, Washton AM. Narcotic antagonists in the treatment of opioide dependence. Comp Psychiat 1979; 20: 116-126.

992 to have milder sedative and hypotensive effects. 6, Evidence of lofexidine’s ability to suppress opiate withdrawal effects has been demonstrated in morphine-dependent rats8but no previous studies have explored its efficacy in opiate-addicted man. Our subjects were fifteen methadone-dependent male outpatient volunteers who showed no evidence of medical or psychiatric illness and gave informed consent to the study which involved an abrupt switch from methadone to lofexidine. On day 1 subjects received their usual methadone dose (10-25 mg) and began a selfadministered lofexidine dose regimen of 0.1 mg two or three times daily. On day 2, methadone was abruptly discontinued with subjects receiving a matched placebo methadone solution and the,lofexidine the dosage was increased to 0 -1mg four times daily. lofexidine dose was increased as needed to no more than 0 -4mg four times daily according to symptoms and side effects. All subjects were told that the detoxification procedure would take 11 days and that naltrexone could be started on day 11 (10 days post methadone) provided that they used no illicit opiates during the study as confirmed by the absence of a precipitated withdrawal reaction to intravenous naloxone challenge (2’0mg) on day 11. Subjects who did use illicit opiates during the first 10 days post methadone were allowed to continue on lofexidine and the naloxone challenge was postponed to the first opportunity where it posed minimal risk of precipitating a withdrawal reaction (i.e., to at least 5 days after the last opiate use) but no later than day 21 of the study. Subjects who passed the naloxone challenge and started naltrexone on days 11-21 were considered successful detoxifications. Those who returned to using opiates and failed to begin naltrexone by day 21 were considered unsuccessful. Successful detoxification and induction onto naltrexone was accomplished with ten of the fifteen subjects. All patients rated lofexidine as moderately to extremely effective in reducing most of the commonly experienced withdrawal symptoms: insomnia, lethargy, and muscle/bone pain were the most frequent residual complaints. None of the ten subjects reported unacceptable withdrawal symptoms while taking lofexidine. Those who failed to complete the detoxification procedure cited opiate craving rather than withdrawal discomfort as the major reason for returning to opiate use. No-one reported oversedation, dizziness, or lightheadedness from lofexidine, despite rapid increases in the dose to as much as 1 - 6 mg per day within the first 5 days. The maximum daily lofexidine dose ranged from 0 -6mg to 1 -6mg across the ten subjects with an average of 1’2 mg. There was no significant lowering of blood pressure even at the maximum lofexidine dose (mean pre-lofexidine BP 115/74 mm Hg; mean BP at maximum dose 115/76 mm Hg). Dry mouth and mild drowsiness were the most commonly reported side effects. Upon study completion, reductions in the daily lofexidine dose by 0’ 2 to 0 -6mg per day

naltrexone or drug free modalities without hospital admission. Double-blind outpatient trials are needed to determine the relative efficacy and usefulness of these two alpha-adrenergic agonists as treatments for opiate withdrawal. access to

We thank Merrell Dow Pharmaceuticals, Inc., for financial ’support and supplies of lofexidine. The assistance of Mr Nicholas Reed and Dr Michael Napoliello of Merrell Dow is greatly appreciated. Division of Drug Abuse Research and Treatment.

Department of Psychiatry, New York Medical College, New York, N.Y. 10029 U.S.A.

ARNOLD M. WASHTON RICHARD B. RESNICK

JOSEPH F. PERZEL, JR JOHN GARWOOD

Subsequently,

no symptomatic complaints or significant changes in blood pressure. This open clinical trial provides preliminary, but strongly suggestive, evidence of lofexidine’s efficacy in reducing opiate withdrawal. The findings are similar to our results with clonidinel-3 in terms of detoxification success rates and withdrawal symptom relief, but lofexidine seems to be considerably less sedating and hypotensive. Lofexidine may therefore prove to be safer and more clinically useful than clonidine, especially in outpatient detoxification. Since lofexidine can be taken in higher doses than clonidine without untoward side effects, it might be possible to detoxify outpatients from higher levels of opiate dependence than has been the case with clonidine. A study of lofexidine’s efficacy with outpatients switched abruptly from increasing doses of methadone might be extremely worthwhile. Our findings suggest that lofexidine might allow opiate-addicted outpatients even greater

produced

6. Maner T, Mehta J, Johnson C, Conti CR. Comparative efficacy of two centrally acting imidazoline derivatives, clonidine and lofexidine. Clin Res 1980; 28: 33A. 7. St. John LaCorte W, Jain AK, Ryan JR, McMahon FG. Comparative efficacy and tolerability of lofexidine and clonidine given alone or concomitantly with hydrochlorothiazide in hypertensive outpatients. Clin Pharmacol Ther 1981; 29: 259. 8. Sherman GT, Lal H, Ursillo RC. Effectiveness of lofexidine in blocking morphinewithdrawal signs in the rat. Pharmacol Biochem Behav 1980; 12: 573-75.

SIR,-We have described potent anti-withdrawal effects for clonidine, the alpha-2 adrenergic agonistl-3 which reduces brain noradrenergic activity. On the basis of clonidine’s efficacy in human opiate withdrawal and preclinical rodent and primate studies we have postulated noradrenergic hyperactivity in opiate withdrawal and predicted that new non-opiate medications with central antinoradrenaline activity might be found which are as potent as clonidine in anti-withdrawal efficacy but without clonidine’s sedative and antihypertensive effects,4and we suggested that lofexidine, an analogue of clonidine, might be an improvement. Lofexidine is a weak antihypertensive agent; it has substantial affinity for clonidine binding sites in brainand is believed to have similar anti-noradrenaline effects in brain without opiate receptor

binding or opiate activity. Data from nine male chronic methadone addicts demonstrate potent anti-withdrawal activity for lofexidine. The patients had been addicted to opiates for 1-10 years and to methadone for 6-80 months. All expressed interest in discontinuing methadone and all gave informed consent to the study which required abrupt discontinuation of methadone and at least 36 h with no opiate administration. All had objective signs of opiate withdrawal and urine specimens showing only residual methadone. The patients were observed for withdrawal signs and symptoms. Withdrawal was assessed by rating nineteen symptoms as severe (3), moderate (2), mild (1), or absent (none) and summing the scores. All patients had signs and symptoms of moderate opiate withdrawal. After lofexidine 3 pg/kg the withdrawal score fell (p>0 &mid otI); 01 ) from 30 -3:t8’6(SEM) to 8 - 2±5 -5at 120 min. Blood pressure was not significantly decreased and remained normal. Pre-lofexidine blood pressure was 121:t 13176:t7 and at 120 min blood pressure was 114±14/80±8. There were no significant changes in alertness, or mood. Anxiolytic activity and relief from subjective distress were dramatic. All nine patients felt that they were in withdrawal or "kicking" before lofexidine administration while none of these patients stated that they were "kicking" at 120 min after lofexidine. All elected to remain in the hospital where they were given lofexidine 20 I-Ig/kg day in divided doses for at least an additional 10 days. During the 14 days of lofexidine administration, there were no significant changesI in withdrawal ratings. The only complaint was occasional difficulty in falling and/or staying asleep. All patients were successfully detoxified from chronic methadone addiction in this inpatient study and were successfully switched to the long-acting opiate antagonist naltrexone. Clonidine, though effective in opiate withdrawal, has sedative and hypotensive properties at the doses needed to reverse methadone withdrawal which limit its use in outpatients.4,6 With lofexidine anti-withdrawal may be separated from anti-hypertensive

sedation,

1. Gold

MS, Redmond DE, Jr, Kleber HD. Clonidine blocks acute opiate withdrawal symptoms. Lancet 1978; ii: 599-601. 2. Gold MS, Pottash ALC, Sweeney DR, Kleber HD. Opiate withdrawal using clonidine a safe, effective and rapid nonopiate treatment. JAMA 1980; 243: 343-46. 3. Gold MS, Pottash ALC, Extern I, Kleber HD. Clonidine in acute opiate withdrawal N

Engl J Med 1980; 302: 1421-22. 4. Gold

MS, Pottash ALC, Extein I, Kleber HD Clonidine and opiate withdrawal Lancet 1980; ii: 1078-79. 5. Jarrott B, Louis WJ, Summers RJ. Effect of aseries of clonidine analogues on clonidine binding in rat cerebral cortex. Biochem Pharmacol 1979, 28: 141-44 6. Gold MS, Pottash ALC, Carter A, Kleber HD Outpatient clonidine detoxification Lancet 1981; i: 621.

993

and sedating effects, though further studies are necessary to confirm dose threshold effect. this and Withdrawal scores were not suppressed to zero and increasing the lofexidine dose to suppress all opiate withdrawal signs and symptoms may produce hypotension and sedation. Nevertheless the demonstration of striking anti-withdrawal efficacy in chronic methadone addicts suggests that in lofexidine we may have a further new treatment for opiate detoxification and for the transition fromopiate dependence to drug-free or naltrexone maintenance. to

establish whether it is

Research Facilities, Fair Oaks Hospital,

Summit, New

Jersey, 07901, U.S.A.;

and Addiction-Prevention Treatment Foundation and Substance Abuse Unit,

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut

a

MARK S. GOLD A. CARTER POTTASH WILLIAM J. ANNITTO IRL EXTEIN HERBERT D. KLEBER

DIFFUSE EXERCISE-INDUCED MUSCLE PAIN OF UNDETERMINED CAUSE RELIEVED BY VERAPAMIL

SIR,-A 35-year-old man was admitted to this neurological centre June 9, 1980. In his late twenties he had first experienced dull painful aching in the calf and thigh muscles, coming on after on

prolonged exertion and generally towards the end of the day. If he rested, the pain would disappear over a few hours, and pain was invariably relieved by a night’s sleep, however prolonged and intense the preceding exertion. Gradually, however, the muscular aching increased and spread, after 3 years, to the thighs, buttocks, and hamstrings and then to the arms, hands, and shoulder girdle muscles. In time the pain became almost constant with only slight relief resulting from rest. His sister, who was 4 years older, had had identical symptoms for the previous 12 years. The patient and his sister were the only children of unrelated, healthy parents and there was no family history of any similar symptoms. The patient was not taking drugs and had no history of drug abuse or excessive alcohol intake. The cardiovascular and respiratory systems and the abdomen seemed normal-as, indeed, did the neuromuscular system on examination. The configuration of the skeletal muscles was normal, they were not tender, and there was no myotonia, no fasciculation, and no myoidema. The consistency of the muscles on palpation appeared normal. Direct myotatic irritability and the tendon reflexes were also normal, and indeed no physical abnormality could be identified. The patient had been extensively investigated in London at Guy’s Hospital and the National Hospital, but was reinvestigated because, by the time he came to Newcastle, his disabling muscle pain was interfering with his ability to work. The many tests did not point to a diagnosis. The following results, for example, were normal: blood lactate rise after ischaemic work; electromyography and nerve conduction velocities including singlefibre electromyography; muscle histology and histochemistry; total muscle glycogen, AMP deaminase (1-06 mol/min/mg protein), carnitine palmityl transferase (25nmol/min/mg of non-collagen protein [NCP]), muscle creatine kinase (11.66 IU/mg NCP), and adenylic kinase (0-427 mol/min/mg NCP); free and total muscle carnitine values (16 -7 and 19.6 6 nmol/mg NCP). Even after prolonged exercise, myoglobinuria could not be detected. .Bùtochondrial function (Dr John Morgan-Hughes, National Hospital) was normal. Electron microscopy of muscle biopsy sections here in Newcastle also showed no morphological abnormality; the mitochondria were normal in size and shape and no tubular aggregates were found. This patient’s condition and that of his sister thus remained unexplained. We have now seen many such patients with symptoms resembling those of McArdle’s disease but in whom we have been .mable to identify a cause. We were satisfied that there was no psychological cause for his symptoms and that he had an

unexplained metabolic myopathy. Many drugs had been tried before he came to Newcastle, and we suggested an empirical trial of others. Powerful analgesics produced some temporary and partial relief, but diazepam, phenytoin, procaine amide, beta-adrenergic "’locking agents, carbamazepine, and many more drugs were

unhelpful. Dantrolene sodium slightly improved the pain, but it also produced substantial muscle weakness and had to be discontinued. Although there was no histological or other evidence of ischaemia of his skeletal muscles, Dr M. B. Holmes decided upon a trial of naftidrofuryl oxalate 100 mg three times daily. Within 48 hours both the patient and his sister found that their muscular pain was greatly increased, and they were confined to bed. After withdrawal of this drug their condition returned to what it had been before, again over 48 hours. Since one effect of the latter drug is to increase intramuscular ATP and to enhance cellular oxidative activity, it seemed reasonable to try verapamil hydrochloride, which reduces the turnover of high-energy phosphates in cardiac muscle and probably in skeletal muscle as well, inhibits movement of calcium across the muscle cell membrane, and decreases muscular requirement for oxygen and the activity of calcium-dependent ATPase. It has been suggested that such an effect of the calcium inhibitor class of drugs might reduce muscle fibre necrosis in degenerative and inflammatory myopathies. Despite the fact that there was no evidence clinically or histologically of muscle fibre necrosis in this case which might be calcium-induced, I suggested to Dr Holmes that he treat the patient with verapamil 60 mg three times daily. The response was immediate and dramatic with remarkable relief of his muscle pain and tenderness within 36 hours, and his sister has been similarly helped. The patient’s dose was increased to 120 mg three times daily with total relief, but at this dose his sister had tachycardia and extrasystoles and the dose was reduced to 60 mg four times daily without any return of muscle pain. Improvement has been sustained in both patients for several weeks. One suggestion (from Prof. J. B. Harris) is that excessive calcium load upon the muscle mitochondria accounted for the pain and that this has been reduced by the verapamil. I would be interested to hear from colleagues who may have some explanation for this remarkable response which must, of course, be confirmed by further trials in similar cases. I thank the patient’s general practitioner, Dr M. B. Holmes of St Brelade’s, Jersey; Dr R. C. Hughes (Guy’s Hospital); and Dr John Morgan-Hughes (National Hospital) for access to reports of investigations done when the

patient was under their care. Regional Neurological Centre, General Hospital, Newcastle upon Tyne NE4 6BE; and Department of Neurology, University of Newcastle upon Tyne

EFFECT OF PARENTAL SMOKING ON CHILDREN

JOHN WALTON IgE LEVELS IN

SIR,-While studying the development of atopic disease in highrisk families’ (where both parents have atopic disease) we looked at the effect of parental smoking on the development of serum IgE levels in 46 children from 0 to 3 years of age. The smoking habits of the parents were assessed by questionnaire when the children were 3, 6, 9, 12, 18, and 36 months of age, and the children were divided into two groups, according to the answers, as coming from non-smoking homes or smoking homes. All the children were given a clinical examination and blood was sampled at most visits. Serum IgE levels were determined using Phadebas ’PRIEST’2on serum kept at -20°C pending analysis. The IgE level rose more rapidly in children from smoking families (figure) and a significant group difference (p<0-05) was seen at 9 and 36 months of age. The scatter of the IgE levels was considerable, which probably explains the lack of significance at 12 and 18 months. This finding accords with recent findings in smoking/nonsmoking adults3 and adds further evidence to the negative effects of Kjellman N-IM, Johansson SGO. Soy versus cow’s milk in infants with a biparental history ofatopic disease: Development of atopic disease and immunoglobulins from birth to 4 years of age Clin Allergy 1979; 9: 347-58. 2. Ceska M, Lundkvist U. A new and simple radioimmunoassay method for the determination of IgE. Immunochemistry 1972; 9: 1021-30. 3. Gerrard JW, Heiner DC, Ko CG, Mink J, Meyers A, Dosman JA. Immunoglobulin levels in smokers and non-smokers. Ann Allergy 1980; 44: 261-62. 1