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Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone treatment for in-patient opiate detoxification
Drug and Alcohol Dependence 50 (1998) 227 – 232
Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone treatment for in-patient opiate detoxification Jennifer Bearn *, Michael Gossop, John Strang National Addiction Centre, The Maudsley Institute of Psychiatry, 4 Windsor Walk, London SE5 8AF, UK Received 20 October 1997; accepted 6 February 1998
Abstract This open study compares an accelerated 5-day lofexidine regimen with orthodox 10-day lofexidine and methadone regimens in the treatment of opiate withdrawal in 61 polysubstance abusing opiate addicts. Significant differences in levels of withdrawal symptoms were found on days 11, 13–15 and 17–20, symptoms resolving most rapidly in the 5-day lofexidine treatment group, whilst withdrawal responses in the 10-day lofexidine treatment group were intermediate between the 5-day lofexidine and standard methadone treatment conditions. When the two lofexidine regimens were separately compared with methadone the 5-day lofexidine treatment was significantly more effective on day 10, 11 and 13 – 20, whilst the 10-day lofexidine treatment was not significantly different from methadone. There were no significant differences in rates of completion of detoxification between the three treatments. Both the lofexidine treatment regimens had a similar effect on blood pressure. Five patients experienced side effects which resolved with dose reduction, all remaining in the study. An accelerated 5-day lofexidine regimen may attenuate opiate withdrawal symptoms more rapidly than conventional 10-day lofexidine or methadone treatment schedules without exacerbating hypotensive side effects. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Polydrug abusers; Opiate withdrawal; Methadone; Lofexidine
1. Introduction Attempts to improve the treatment of opiate detoxification have in recent years focused on the use of safer non-opiate alternatives to methadone and on accelerating the resolution of withdrawal symptoms. The main non-opiate treatments available are the a-2 adrenergic agonists, clonidine and lofexidine. Whilst they appear equally effective in ameliorating withdrawal symptoms (Kahn et al., 1997), clonidine is associated with side effects, notably postural hypotension and sedation (Charney et al., 1981; Gossop, 1988) which limits its clinical application to in-patient treat* Corresponding author. Present address: Wickham Park House, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent BR3 3BX, UK. Tel.: +44 181 7764116; fax: + 44 181 7762076.
ment settings. In contrast, lofexidine is only sporadically associated with hypotension (Bearn et al., 1996; Kahn et al., 1997; Lin et al., 1997) which can be controlled by dose adjustment enabling it also to be applied in out-patient and community settings (Wylie and Stewart, 1995). When it was first licensed for clinical use in 1992, concerns about potential hypotensive side effects led to recommendations that lofexidine should be initiated using incremental doses in the first few days of treatment (Britlofex Data Sheet, Britannia Pharmaceuticals). More recent clinical experience suggests that such caution is unnecessary and that full therapeutic doses can be initiated immediately without adverse effects (Cook, Finch, personal communication). In the past, in-patient detoxification treatment was often carried out over a period of 3 or more weeks (Gossop et al., 1987). When it was demonstrated that
0376-8716/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0376-8716(98)00030-1
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Table 1 Clinical characteristics of patients in the three study conditions
Mean age % Male Total opiate dose (mg) Total benzodiazepine dose (mg)
10-Day lofexidine treatment (n= 20)
10-Day methadone treatment (n =19)
5-Day lofexidine treatment (n =22)
Statistic
P
30.2 85 65.3 45.0
32.9 84 65.5 33.9
32.3 86 56.0 40.0
F =1.11 x 2 =0.39 F =0.91 F =0.44
0.33 0.98 0.41 0.65
reducing treatment duration from 21 to 10 days did not substantially increase the severity of withdrawal symptoms (Gossop et al., 1989), routine 10-day treatment schedules were adopted into standard clinical practice. At present both clonidine and lofexidine are routinely administered for 10– 16 days to in-patients (Gold et al., 1981; Gossop, 1988). This paper presents an evaluation of the efficacy of lofexidine for enhancing both the speed and efficiency of withdrawal treatment using a modified high dose regimen. This study uses an open design with a patient preference treatment allocation, to compare an accelerated 5 day lofexidine regimen with orthodox 10 day lofexidine and methadone treatments.
2. Methodology
2.1. Patients A total of 61 patients who fulfilled DSM-IV criteria (American Psychiatric Association) for opiate dependence and who had been referred for in-patient detoxification took part in the study. All patients presented with a history of current dependence on heroin or methadone or both, which was supported by laboratory results from urine drug screening, using both chromatographic and radioimmunoassay methods (Screening for drugs of abuse, 1987). We assessed the total opiate use (combined methadone and heroin use) by patients on entry to the study by summating the daily methadone requirement and heroin use, using the conversion formula that 1 g of street heroin daily is the equivalent of 60 mg of methadone daily. This conversion formula is widely applied by addiction treatment clinicians in the United Kingdom. A total of 24 patients (39% of the sample) were also regularly using benzodiazepines on admission, the diazepam dose equivalence ranging from 10 – 85 mg diazepam daily. There was no difference between the three treatment groups in the mean methadone equivalence on which patients were dependent prior to detoxification or benzodiazepine use (Table 1). All patients provided informed written consent to participate in the study. Prior to entry, each underwent a full physical examination including lying and standing
blood pressure, full blood count, clinical chemistry profile and ascertainment of Hepatitis B and C antibody status. Patients were excluded if they had serious physical illness, major psychiatric illness, were pregnant or taking neuroleptic or anti-depressant medication. Whilst patients co-dependent on benzodiazepines were included, patients using cocaine regularly (greater than 3 g per week) were excluded because of the interaction between lofexidine and tricyclic antidepressants, routinely used to treat the cocaine withdrawal syndrome.
2.2. Study design On admission all patients underwent a 3-day stabilisation period whereby the amount of methadone given was titrated against objective and subjective symptoms, taking into account the amount of opiates being consumed prior to admission. The two lofexidine treatment regimens were compared by implementing them serially to minimise the possible influence of non-specific factors which might have arisen if patients had undergone different lengths of withdrawal treatment alongside each other. However, we recruited patients into the 10 day methadone treatment condition concurrently with the 10-day lofexidine treatment, the choice of treatment depending on individual patient preference. The patients then selected either the lofexidine or standard methadone treatment schedules. Both patients and staff were open to the identity of the treatment. A total of 22 patients received the 5-day lofexidine treatment regimen (20% of the total number of patients admitted over the study period), 20 received the 10-day lofexidine treatment regimen and 19 received the 10-day methadone treatment regimen (30% of the total number of admissions). There were no differences between the three groups with regard to age and sex (Table 1). For the methadone detoxification, the starting dose of methadone was determined by the mean daily dose requirement during the stabilisation period and the dose reduced to zero at a linear rate over 10 days (Strang and Gossop, 1990). The methadone was progressively diluted to maintain a constant volume of administered liquid. Patients were blind to the initial amount of methadone prescribed.
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229
Fig. 1. Opiate withdrawal responses under treatment with lofexidine and methadone.
The patients allocated to the standard 10 day lofexidine regimen were treated in accordance with the lofexidine (Britlofex) data sheet (Britannia Pharmaceuticals). On the first day they received 0.6 mg lofexidine and thereafter the dose was increased by 0.4 mg daily until day 4; the dose was then maintained at 2 mg daily for 3 days. During the last 3 days of treatment the dose was reduced by 0.4 mg daily. During treatment, patients were permitted an additional 0.4 mg lofexidine in any 24 h period to further ameliorate withdrawal symptoms, which was available at their request. Conversely, in a few cases lofexidine was administered in lower doses to reduce the intensity of side effects. Patients treated with the accelerated lofexidine regimen for 5 days received 1.8 mg of lofexidine in three divided doses on the first day, then 1 mg twice a day for 3 days and 0.6 mg twice a day on the final day of treatment. The patients were permitted an additional 0.4 mg lofexidine during any 24 h period on request. In those patients taking lofexidine, standing and lying blood pressures were measured immediately before each treatment administration. If there was significant postural hypotension (a difference of more than 30 mmHg between lying and standing systolic blood pressure) or an absolute systolic blood pressure of less than 80 Hg, treatment was withheld until the blood pressure had normalised. Patients co-dependent on benzodiazepines were stabilised on diazepam for 3 days before starting concurrent detoxification using a linear dose reduction of diazepam over 14–21 days, depending on their initial severity of dependence. Withdrawal symptom severity was measured using the 10-item short opiate withdrawal scale (SOWS) (Gossop, 1990), a self-rating symptom check list which has been found to provide a reliable and valid measure
of the opiate withdrawal syndrome. The ten SOWS items were: nausea, stomach cramps, muscle spasms, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes, problems sleeping, each of which is rated on a 4 point scale (0 =nil, 1= mild, 2= moderate and 3= severe). The SOWS was completed daily at about 10.00 a.m. for 20 days from the first day of withdrawal treatment. Compliance with treatment and drug status were corroborated by urine drug screening three times a week. The demographic data, dependence characteristics, withdrawal symptom severity and treatment survival rates were compared between the three groups using analysis of variance, and comparisons between two treatment groups were made using t-tests, both with a 95% significance threshold.
3. Results The opiate withdrawal responses for the 5 day lofexidine, 10 day lofexidine and 10 day methadone treatment groups are shown in Fig. 1. Differences in withdrawal severity can be clearly seen in the immediate post-treatment withdrawal phase. Significant differences in levels of withdrawal distress between the three treatments were found on days 11, 13–15 and 17–20 inclusive. Resolution of the withdrawal symptoms was most rapid in the 5 day lofexidine treatment group, whilst the withdrawal responses in the 10 day lofexidine treatment group were intermediate between the short lofexidine and standard methadone treatment conditions. After 8 days the severity of withdrawal symptoms of the patients receiving the 5 day lofexidine treatment had dropped to a level only reached by the methadone group at 20 days. During the first 10 days of treatment
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Table 2 Completion of detoxification and length of stay in treatment 10-Day lofexidine treatment (n= 20) % Completed detox 75 Mean length of stay 19.8 (days)
10-Day methadone treatment (n= 19)
5-Day lofexidine treatment (n =22)
Statistic
P
84 18.7
77 20.0
x 2 =0.53 F = 0.13
0.78 0.88
there were no significant differences between the three groups. Withdrawal symptoms were more severe on day 7 in the 5 day lofexidine group though this difference failed to reach statistical significance at the 5% level (P=0.056). When the two lofexidine regimens were separately compared with methadone treatment, there were significant differences in withdrawal symptom severity. The 5 day lofexidine treatment was significantly more effective at most post-treatment points (day 10, 11 and 13 – 20 inclusive). In contrast, the 10 day lofexidine treatment was not markedly different in clinical efficacy to methadone, being significantly more effective only on day 17. When the 5 and 10 day lofexidine treatments were directly compared, statistical significance to the clinical efficacy of the 5-day lofexidine treatment was confined to a single time point (day 14). The main indicators of treatment compliance were rates of completion of detoxification and length of stay in treatment (Table 2). There was no significant difference in numbers of patients completing treatment, whilst the average length of stay in the three groups was similar, ranging from 18.7 to 20.0 days. The mean standing systolic and diastolic blood pressures for the two lofexidine treatment groups are shown in Fig. 2. There were no significant differences between the two treatments at any point. Two patients in the 10 day lofexidine treatment group, (one male and one female) experienced side effects necessitating dose reduction. The female patient had postural hypotension which resolved when the ceiling dose of lofexidine was reduced to 1.2 mg, whilst the male patient experienced sedation, dry mouth and dizziness, although significant postural hypotension could not be detected. These side effects were relieved when the ceiling dose was reduced to 1.6 mg. In the accelerated 5-day lofexidine treatment group, three patients had side effects severe enough to warrant treatment modification. They were all male, two experiencing dizziness due to postural hypotension and one severe sedation. In every case, dose reduction immediately attenuated side effects so that none of these patients needed to be withdrawn from the study. Ten patients in the 10 day lofexidine treatment group elected to take extra lofexidine (Table 3). There were no requests for additional medication beyond day 4. Ten patients in the 5 day treatment group also requested
additional lofexidine (Table 3) which was confined to the first 6 days of treatment. In the first 3 days, requests for extra lofexidine were comparable between the two groups, although later on the 5-day treatment group made more requests. On day 4, five patients undergoing the 10 day treatment asked for additional lofexidine compared to eight in the 5-day group. On the fifth day, four patients in the accelerated group also needed additional lofexidine, whilst no-one undergoing 10 days of treatment asked for more.
4. Discussion The immediate initiation of lofexidine at a full therapeutic dose, for a period of 5 days, was found to lead to a more rapid rate of resolution of withdrawal symptoms than the traditional 10 day methadone treatment schedule. Indeed, the mean level of withdrawal symptoms 8 days after the start of the 5 day lofexidine treatment had fallen to levels only achieved in the methadone treatment group after an additional 12 day recovery period. The more rapid resolution of the course of the withdrawal syndrome was achieved without any statistically significant increase in withdrawal severity or reduction in retention in treatment. However, there is a trend for symptoms to be worse on day 7; whether this is a real difference between the two treatments requires further investigation by means of a controlled study. In contrast, the conventional 10 day lofexidine treatment schedule was clinically equivalent to the 10 day methadone schedule. When lofexidine was first introduced in 1992, prescribing recommendations stipulated a gradual increase in dose, enabling full therapeutic doses to be achieved after 4 days. This was mainly due to concerns that rapid induction onto a high dose of lofexidine would cause hypotension, although clinical studies preceding its introduction into clinical practice suggested that lofexidine did not substantially adversely affect blood pressure (Gold et al., 1981; Washton and Resnick, 1982; Washton et al., 1983). Later studies have supported these early findings. We have previously shown that lofexidine was broadly equivalent in symptom relief whilst having no significant hypotensive effect compared with metha-
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231
Fig. 2. Mean morning and evening standing systolic and diastolic blood pressures during 5-day and 10-day lofexidine detoxification.
done in a double-blind study comparing clinical efficacy of lofexidine with methadone (Bearn et al., 1996). The findings with these two study conditions (10-day lofexidine and 10-day methadone) in the current study are strikingly similar. In our earlier study, lofexidine was given in incremental doses up to a ceiling of 2 mg daily, the treatment lasting 10 days overall. Clinically, lofexiTable 3 Additional lofexidine treatment Treatment day
Number of patients receiving additional lofexidine
Amount of additional lofexidine/mg
10-Day treatment regimen 1 2 2 3 3 3 4
4 3 2 4 2 1 5
0.2 0.2 0.4 0.2 0.4 0.6 0.2
5-Day treatment regimen 1 1 2 2 3 3 4 4 5 5 6
1 1 4 1 3 2 7 1 3 1 1
0.2 0.4 0.2 0.4 0.2 0.4 0.2 0.4 0.2 0.4 0.2
dine is designed to be prescribed flexibly so that dosage administration can be titrated against withdrawal symptoms and side effects, but the double-blind study design precluded flexible prescribing. This constraint may have lead to some patients receiving sub-optimal treatment. However, in the present study, flexible prescribing was permitted and the effects of lofexidine on withdrawal symptoms are likely to more closely reflect the effects of a more clinically naturalistic application of treatment. Kahn et al. (1997) have shown that lofexidine is significantly less hypotensive than clonidine, the alternative a-2 adrenergic agonist available for treatment of opiate withdrawal. In this study, lofexidine was also introduced gradually in increments of 0.4 mg daily to a ceiling of 1.8 mg, a slightly lower dose than that used in the present study. In both of the previous controlled trials there was an initial period of progressive dosage increments and it is possible that this may have attenuated potential hypotensive side effects of lofexidine. The results of the present study suggest that this need not be a major problem since with the immediate introduction of full therapeutic doses of lofexidine, there was no overall difference in blood pressure responses between the conventional and accelerated treatment regimens. In our previous study (Bearn et al., 1996), two patients out of 42 experienced dizziness due to postural hypotension during lofexidine treatment. In both cases, symptoms resolved when the dose of lofexidine was reduced, treatment continuing at a lower daily dose and neither of the patients needed to be withdrawn from treatment. In the present study, four patients treated with lofexidine experienced dizziness, postural hypoten-
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sion being documented in three. This represents 7.1% of the total number of patients receiving lofexidine treatment. In the context of this sporadic side effect, we recommend the routine measurement of supine and standing blood pressure during lofexidine treatment. Whilst there was a transient rise in blood pressure associated with the more abrupt withdrawal of lofexidine after 5 days of treatment, this was neither clinically nor statistically significant. Whilst a few patients were unable to tolerate full therapeutic doses of lofexidine because of limiting side effects, about half of the patients in each group elected to take additional lofexidine during the first few days of treatment. This study provides further evidence for a spectrum of clinical responsiveness to lofexidine, best served by flexible prescribing according to clinical need. Our findings are subject to several caveats. The patients themselves chose whether or not to participate in the 5-day lofexidine study, and later to opt for either lofexidine or methadone treatment. It is therefore possible that there were intrinsic differences in the treatment expectations, tolerance of withdrawal symptoms and commitment to achieving abstinence in those patients electing to undergo a shorter detoxification regimen. These factors may also have influenced treatment retention. In view of the open study design, nursing staff perceptions and opinions of the different treatments may also have influenced the patient’s experiences. However, these preliminary findings suggest that lofexidine treatment at immediate full therapeutic dosage for a shorter period of time may accelerate the resolution of the opiate withdrawal syndrome in a manner acceptable to patients. A formal double-blind controlled trial is indicated to confirm our preliminary findings. If this confirms that the 5-day lofexidine treatment regimen does accelerate recovery without significant increase in hypotensive complications, then it would permit earlier participation in relapse prevention and rehabilitation treatment programmes, thus maximising the efficiency of utilisation of scarce in-patient detoxification resources.
.
Acknowledgements We are grateful to Britannia Pharmaceuticals for support.
References Bearn, J.A., Gossop, M., Strang, J., 1996. A randomised double-blind comparison of iofexidine and methadone in the in-patient treatment of opiate withdrawal. Drug Alcohol Depend. 43, 87–91. Charney, D.S., Sternberg, D.E., Kleber, H.D., Heninger, G.R., Redmond, D.E., 1981. The clinical use of clonidine in abrupt withdrawal from methadone: effects on blood pressure and specific signs and symptoms. Arch. Gen. Psychiatr. 38, 273 – 277. Gold, M.S., Pottash, A.C., Sweeney, D.R., Extein, I., Annitto, W.J., 1981. Opiate detoxification with lofexidine. Drug Alcohol Depend. 8, 307 – 315. Gossop, M., 1988. Clonidine and the treatment of the opiate withdrawal syndrome. Drug Alcohol Depend. 21, 253 – 259. Gossop, M., 1990. The development of a short opiate withdrawal scale (SOWS). Addict. Behav. 15, 487 – 490. Gossop, M., Bradley, B., Phillips, G.T., 1987. An investigation of withdrawal symptoms shown by opiate addicts during and subsequent to a 21 day in-patient methadone detoxification procedure. Addict. Behav. 12, 1 – 6. Gossop, M., Grifffiths, P., Bradley, B., Strang, J., 1989. Opiate withdrawal symptoms in response to 10-day and 21-day methadone withdrawal programmes. Br. J. Psychiatr. 154, 360–363. Kahn, A., Mumford, J.P., Ash-Rogers, G., Beckford, H., 1997. Double-blind study of lofexidine and clonidine in the detoxification of opiate addicts. Drug Alcohol Depend. 44, 57 – 61. Lin, S.-K., Strang, J., Su, L.-W., Tsai, C.-J., Hu, W.M., 1997. Double-blind randomised controlled trial of lofexidine versus clonidine in the treatment of heroin withdrawal. Drug Alcohol Depend. 48, 127 – 133. Screening for drugs of abuse (editorial), 1987. Lancet 1, 365–366. Strang and Gossop, 1990. Comparison of linear versus inverse exponential methadone reduction curves in the detoxification of opiate addicts. Addict. Behav. 15, 541 – 547. Washton, A.M., Resnick, R.B., 1982. Lofexidine in abrupt methadone withdrawal. Psychopharmacol. Bull. 18, 220 – 221. Washton, A.M., Resnick, R.B., Geyer, G., 1983. Opiate withdrawal using lofexidine — a clonidine analogue with fewer side effect. J. Clin. Psychiatry 44, 335 – 337. Wylie, A.S., Stewart, A.M., 1995. Lofexidine based regimen for opiate addicts. Br. J. Gen. Pract. 45, 217.
Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone treatment for in-patient opiate detoxification Jennifer Bearn *, Michael Gossop, John Strang National Addiction Centre, The Maudsley Institute of Psychiatry, 4 Windsor Walk, London SE5 8AF, UK Received 20 October 1997; accepted 6 February 1998
Abstract This open study compares an accelerated 5-day lofexidine regimen with orthodox 10-day lofexidine and methadone regimens in the treatment of opiate withdrawal in 61 polysubstance abusing opiate addicts. Significant differences in levels of withdrawal symptoms were found on days 11, 13–15 and 17–20, symptoms resolving most rapidly in the 5-day lofexidine treatment group, whilst withdrawal responses in the 10-day lofexidine treatment group were intermediate between the 5-day lofexidine and standard methadone treatment conditions. When the two lofexidine regimens were separately compared with methadone the 5-day lofexidine treatment was significantly more effective on day 10, 11 and 13 – 20, whilst the 10-day lofexidine treatment was not significantly different from methadone. There were no significant differences in rates of completion of detoxification between the three treatments. Both the lofexidine treatment regimens had a similar effect on blood pressure. Five patients experienced side effects which resolved with dose reduction, all remaining in the study. An accelerated 5-day lofexidine regimen may attenuate opiate withdrawal symptoms more rapidly than conventional 10-day lofexidine or methadone treatment schedules without exacerbating hypotensive side effects. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Polydrug abusers; Opiate withdrawal; Methadone; Lofexidine
1. Introduction Attempts to improve the treatment of opiate detoxification have in recent years focused on the use of safer non-opiate alternatives to methadone and on accelerating the resolution of withdrawal symptoms. The main non-opiate treatments available are the a-2 adrenergic agonists, clonidine and lofexidine. Whilst they appear equally effective in ameliorating withdrawal symptoms (Kahn et al., 1997), clonidine is associated with side effects, notably postural hypotension and sedation (Charney et al., 1981; Gossop, 1988) which limits its clinical application to in-patient treat* Corresponding author. Present address: Wickham Park House, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent BR3 3BX, UK. Tel.: +44 181 7764116; fax: + 44 181 7762076.
ment settings. In contrast, lofexidine is only sporadically associated with hypotension (Bearn et al., 1996; Kahn et al., 1997; Lin et al., 1997) which can be controlled by dose adjustment enabling it also to be applied in out-patient and community settings (Wylie and Stewart, 1995). When it was first licensed for clinical use in 1992, concerns about potential hypotensive side effects led to recommendations that lofexidine should be initiated using incremental doses in the first few days of treatment (Britlofex Data Sheet, Britannia Pharmaceuticals). More recent clinical experience suggests that such caution is unnecessary and that full therapeutic doses can be initiated immediately without adverse effects (Cook, Finch, personal communication). In the past, in-patient detoxification treatment was often carried out over a period of 3 or more weeks (Gossop et al., 1987). When it was demonstrated that
0376-8716/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0376-8716(98)00030-1
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Table 1 Clinical characteristics of patients in the three study conditions
Mean age % Male Total opiate dose (mg) Total benzodiazepine dose (mg)
10-Day lofexidine treatment (n= 20)
10-Day methadone treatment (n =19)
5-Day lofexidine treatment (n =22)
Statistic
P
30.2 85 65.3 45.0
32.9 84 65.5 33.9
32.3 86 56.0 40.0
F =1.11 x 2 =0.39 F =0.91 F =0.44
0.33 0.98 0.41 0.65
reducing treatment duration from 21 to 10 days did not substantially increase the severity of withdrawal symptoms (Gossop et al., 1989), routine 10-day treatment schedules were adopted into standard clinical practice. At present both clonidine and lofexidine are routinely administered for 10– 16 days to in-patients (Gold et al., 1981; Gossop, 1988). This paper presents an evaluation of the efficacy of lofexidine for enhancing both the speed and efficiency of withdrawal treatment using a modified high dose regimen. This study uses an open design with a patient preference treatment allocation, to compare an accelerated 5 day lofexidine regimen with orthodox 10 day lofexidine and methadone treatments.
2. Methodology
2.1. Patients A total of 61 patients who fulfilled DSM-IV criteria (American Psychiatric Association) for opiate dependence and who had been referred for in-patient detoxification took part in the study. All patients presented with a history of current dependence on heroin or methadone or both, which was supported by laboratory results from urine drug screening, using both chromatographic and radioimmunoassay methods (Screening for drugs of abuse, 1987). We assessed the total opiate use (combined methadone and heroin use) by patients on entry to the study by summating the daily methadone requirement and heroin use, using the conversion formula that 1 g of street heroin daily is the equivalent of 60 mg of methadone daily. This conversion formula is widely applied by addiction treatment clinicians in the United Kingdom. A total of 24 patients (39% of the sample) were also regularly using benzodiazepines on admission, the diazepam dose equivalence ranging from 10 – 85 mg diazepam daily. There was no difference between the three treatment groups in the mean methadone equivalence on which patients were dependent prior to detoxification or benzodiazepine use (Table 1). All patients provided informed written consent to participate in the study. Prior to entry, each underwent a full physical examination including lying and standing
blood pressure, full blood count, clinical chemistry profile and ascertainment of Hepatitis B and C antibody status. Patients were excluded if they had serious physical illness, major psychiatric illness, were pregnant or taking neuroleptic or anti-depressant medication. Whilst patients co-dependent on benzodiazepines were included, patients using cocaine regularly (greater than 3 g per week) were excluded because of the interaction between lofexidine and tricyclic antidepressants, routinely used to treat the cocaine withdrawal syndrome.
2.2. Study design On admission all patients underwent a 3-day stabilisation period whereby the amount of methadone given was titrated against objective and subjective symptoms, taking into account the amount of opiates being consumed prior to admission. The two lofexidine treatment regimens were compared by implementing them serially to minimise the possible influence of non-specific factors which might have arisen if patients had undergone different lengths of withdrawal treatment alongside each other. However, we recruited patients into the 10 day methadone treatment condition concurrently with the 10-day lofexidine treatment, the choice of treatment depending on individual patient preference. The patients then selected either the lofexidine or standard methadone treatment schedules. Both patients and staff were open to the identity of the treatment. A total of 22 patients received the 5-day lofexidine treatment regimen (20% of the total number of patients admitted over the study period), 20 received the 10-day lofexidine treatment regimen and 19 received the 10-day methadone treatment regimen (30% of the total number of admissions). There were no differences between the three groups with regard to age and sex (Table 1). For the methadone detoxification, the starting dose of methadone was determined by the mean daily dose requirement during the stabilisation period and the dose reduced to zero at a linear rate over 10 days (Strang and Gossop, 1990). The methadone was progressively diluted to maintain a constant volume of administered liquid. Patients were blind to the initial amount of methadone prescribed.
J. Bearn et al. / Drug and Alcohol Dependence 50 (1998) 227–232
229
Fig. 1. Opiate withdrawal responses under treatment with lofexidine and methadone.
The patients allocated to the standard 10 day lofexidine regimen were treated in accordance with the lofexidine (Britlofex) data sheet (Britannia Pharmaceuticals). On the first day they received 0.6 mg lofexidine and thereafter the dose was increased by 0.4 mg daily until day 4; the dose was then maintained at 2 mg daily for 3 days. During the last 3 days of treatment the dose was reduced by 0.4 mg daily. During treatment, patients were permitted an additional 0.4 mg lofexidine in any 24 h period to further ameliorate withdrawal symptoms, which was available at their request. Conversely, in a few cases lofexidine was administered in lower doses to reduce the intensity of side effects. Patients treated with the accelerated lofexidine regimen for 5 days received 1.8 mg of lofexidine in three divided doses on the first day, then 1 mg twice a day for 3 days and 0.6 mg twice a day on the final day of treatment. The patients were permitted an additional 0.4 mg lofexidine during any 24 h period on request. In those patients taking lofexidine, standing and lying blood pressures were measured immediately before each treatment administration. If there was significant postural hypotension (a difference of more than 30 mmHg between lying and standing systolic blood pressure) or an absolute systolic blood pressure of less than 80 Hg, treatment was withheld until the blood pressure had normalised. Patients co-dependent on benzodiazepines were stabilised on diazepam for 3 days before starting concurrent detoxification using a linear dose reduction of diazepam over 14–21 days, depending on their initial severity of dependence. Withdrawal symptom severity was measured using the 10-item short opiate withdrawal scale (SOWS) (Gossop, 1990), a self-rating symptom check list which has been found to provide a reliable and valid measure
of the opiate withdrawal syndrome. The ten SOWS items were: nausea, stomach cramps, muscle spasms, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes, problems sleeping, each of which is rated on a 4 point scale (0 =nil, 1= mild, 2= moderate and 3= severe). The SOWS was completed daily at about 10.00 a.m. for 20 days from the first day of withdrawal treatment. Compliance with treatment and drug status were corroborated by urine drug screening three times a week. The demographic data, dependence characteristics, withdrawal symptom severity and treatment survival rates were compared between the three groups using analysis of variance, and comparisons between two treatment groups were made using t-tests, both with a 95% significance threshold.
3. Results The opiate withdrawal responses for the 5 day lofexidine, 10 day lofexidine and 10 day methadone treatment groups are shown in Fig. 1. Differences in withdrawal severity can be clearly seen in the immediate post-treatment withdrawal phase. Significant differences in levels of withdrawal distress between the three treatments were found on days 11, 13–15 and 17–20 inclusive. Resolution of the withdrawal symptoms was most rapid in the 5 day lofexidine treatment group, whilst the withdrawal responses in the 10 day lofexidine treatment group were intermediate between the short lofexidine and standard methadone treatment conditions. After 8 days the severity of withdrawal symptoms of the patients receiving the 5 day lofexidine treatment had dropped to a level only reached by the methadone group at 20 days. During the first 10 days of treatment
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Table 2 Completion of detoxification and length of stay in treatment 10-Day lofexidine treatment (n= 20) % Completed detox 75 Mean length of stay 19.8 (days)
10-Day methadone treatment (n= 19)
5-Day lofexidine treatment (n =22)
Statistic
P
84 18.7
77 20.0
x 2 =0.53 F = 0.13
0.78 0.88
there were no significant differences between the three groups. Withdrawal symptoms were more severe on day 7 in the 5 day lofexidine group though this difference failed to reach statistical significance at the 5% level (P=0.056). When the two lofexidine regimens were separately compared with methadone treatment, there were significant differences in withdrawal symptom severity. The 5 day lofexidine treatment was significantly more effective at most post-treatment points (day 10, 11 and 13 – 20 inclusive). In contrast, the 10 day lofexidine treatment was not markedly different in clinical efficacy to methadone, being significantly more effective only on day 17. When the 5 and 10 day lofexidine treatments were directly compared, statistical significance to the clinical efficacy of the 5-day lofexidine treatment was confined to a single time point (day 14). The main indicators of treatment compliance were rates of completion of detoxification and length of stay in treatment (Table 2). There was no significant difference in numbers of patients completing treatment, whilst the average length of stay in the three groups was similar, ranging from 18.7 to 20.0 days. The mean standing systolic and diastolic blood pressures for the two lofexidine treatment groups are shown in Fig. 2. There were no significant differences between the two treatments at any point. Two patients in the 10 day lofexidine treatment group, (one male and one female) experienced side effects necessitating dose reduction. The female patient had postural hypotension which resolved when the ceiling dose of lofexidine was reduced to 1.2 mg, whilst the male patient experienced sedation, dry mouth and dizziness, although significant postural hypotension could not be detected. These side effects were relieved when the ceiling dose was reduced to 1.6 mg. In the accelerated 5-day lofexidine treatment group, three patients had side effects severe enough to warrant treatment modification. They were all male, two experiencing dizziness due to postural hypotension and one severe sedation. In every case, dose reduction immediately attenuated side effects so that none of these patients needed to be withdrawn from the study. Ten patients in the 10 day lofexidine treatment group elected to take extra lofexidine (Table 3). There were no requests for additional medication beyond day 4. Ten patients in the 5 day treatment group also requested
additional lofexidine (Table 3) which was confined to the first 6 days of treatment. In the first 3 days, requests for extra lofexidine were comparable between the two groups, although later on the 5-day treatment group made more requests. On day 4, five patients undergoing the 10 day treatment asked for additional lofexidine compared to eight in the 5-day group. On the fifth day, four patients in the accelerated group also needed additional lofexidine, whilst no-one undergoing 10 days of treatment asked for more.
4. Discussion The immediate initiation of lofexidine at a full therapeutic dose, for a period of 5 days, was found to lead to a more rapid rate of resolution of withdrawal symptoms than the traditional 10 day methadone treatment schedule. Indeed, the mean level of withdrawal symptoms 8 days after the start of the 5 day lofexidine treatment had fallen to levels only achieved in the methadone treatment group after an additional 12 day recovery period. The more rapid resolution of the course of the withdrawal syndrome was achieved without any statistically significant increase in withdrawal severity or reduction in retention in treatment. However, there is a trend for symptoms to be worse on day 7; whether this is a real difference between the two treatments requires further investigation by means of a controlled study. In contrast, the conventional 10 day lofexidine treatment schedule was clinically equivalent to the 10 day methadone schedule. When lofexidine was first introduced in 1992, prescribing recommendations stipulated a gradual increase in dose, enabling full therapeutic doses to be achieved after 4 days. This was mainly due to concerns that rapid induction onto a high dose of lofexidine would cause hypotension, although clinical studies preceding its introduction into clinical practice suggested that lofexidine did not substantially adversely affect blood pressure (Gold et al., 1981; Washton and Resnick, 1982; Washton et al., 1983). Later studies have supported these early findings. We have previously shown that lofexidine was broadly equivalent in symptom relief whilst having no significant hypotensive effect compared with metha-
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Fig. 2. Mean morning and evening standing systolic and diastolic blood pressures during 5-day and 10-day lofexidine detoxification.
done in a double-blind study comparing clinical efficacy of lofexidine with methadone (Bearn et al., 1996). The findings with these two study conditions (10-day lofexidine and 10-day methadone) in the current study are strikingly similar. In our earlier study, lofexidine was given in incremental doses up to a ceiling of 2 mg daily, the treatment lasting 10 days overall. Clinically, lofexiTable 3 Additional lofexidine treatment Treatment day
Number of patients receiving additional lofexidine
Amount of additional lofexidine/mg
10-Day treatment regimen 1 2 2 3 3 3 4
4 3 2 4 2 1 5
0.2 0.2 0.4 0.2 0.4 0.6 0.2
5-Day treatment regimen 1 1 2 2 3 3 4 4 5 5 6
1 1 4 1 3 2 7 1 3 1 1
0.2 0.4 0.2 0.4 0.2 0.4 0.2 0.4 0.2 0.4 0.2
dine is designed to be prescribed flexibly so that dosage administration can be titrated against withdrawal symptoms and side effects, but the double-blind study design precluded flexible prescribing. This constraint may have lead to some patients receiving sub-optimal treatment. However, in the present study, flexible prescribing was permitted and the effects of lofexidine on withdrawal symptoms are likely to more closely reflect the effects of a more clinically naturalistic application of treatment. Kahn et al. (1997) have shown that lofexidine is significantly less hypotensive than clonidine, the alternative a-2 adrenergic agonist available for treatment of opiate withdrawal. In this study, lofexidine was also introduced gradually in increments of 0.4 mg daily to a ceiling of 1.8 mg, a slightly lower dose than that used in the present study. In both of the previous controlled trials there was an initial period of progressive dosage increments and it is possible that this may have attenuated potential hypotensive side effects of lofexidine. The results of the present study suggest that this need not be a major problem since with the immediate introduction of full therapeutic doses of lofexidine, there was no overall difference in blood pressure responses between the conventional and accelerated treatment regimens. In our previous study (Bearn et al., 1996), two patients out of 42 experienced dizziness due to postural hypotension during lofexidine treatment. In both cases, symptoms resolved when the dose of lofexidine was reduced, treatment continuing at a lower daily dose and neither of the patients needed to be withdrawn from treatment. In the present study, four patients treated with lofexidine experienced dizziness, postural hypoten-
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sion being documented in three. This represents 7.1% of the total number of patients receiving lofexidine treatment. In the context of this sporadic side effect, we recommend the routine measurement of supine and standing blood pressure during lofexidine treatment. Whilst there was a transient rise in blood pressure associated with the more abrupt withdrawal of lofexidine after 5 days of treatment, this was neither clinically nor statistically significant. Whilst a few patients were unable to tolerate full therapeutic doses of lofexidine because of limiting side effects, about half of the patients in each group elected to take additional lofexidine during the first few days of treatment. This study provides further evidence for a spectrum of clinical responsiveness to lofexidine, best served by flexible prescribing according to clinical need. Our findings are subject to several caveats. The patients themselves chose whether or not to participate in the 5-day lofexidine study, and later to opt for either lofexidine or methadone treatment. It is therefore possible that there were intrinsic differences in the treatment expectations, tolerance of withdrawal symptoms and commitment to achieving abstinence in those patients electing to undergo a shorter detoxification regimen. These factors may also have influenced treatment retention. In view of the open study design, nursing staff perceptions and opinions of the different treatments may also have influenced the patient’s experiences. However, these preliminary findings suggest that lofexidine treatment at immediate full therapeutic dosage for a shorter period of time may accelerate the resolution of the opiate withdrawal syndrome in a manner acceptable to patients. A formal double-blind controlled trial is indicated to confirm our preliminary findings. If this confirms that the 5-day lofexidine treatment regimen does accelerate recovery without significant increase in hypotensive complications, then it would permit earlier participation in relapse prevention and rehabilitation treatment programmes, thus maximising the efficiency of utilisation of scarce in-patient detoxification resources.
.
Acknowledgements We are grateful to Britannia Pharmaceuticals for support.
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