This is the first published placebo-controlled (PC), double-blind (DB), randomized clinical trial (RCT) evaluating the tolerability and the efficacy of lofexidine in the treatment of opioid withdrawal symptoms. The study demonstrates that lofexidine (3.2 mg/day, p.o.) compared with placebo significantly decreases the signs and symptoms of opioid withdrawal in opioid dependent individuals in an inpatient setting. Moreover, the retention of the lofexidine subjects was significantly greater than the retention of the placebo subjects during treatment. Lofexidine decreased both systolic and diastolic blood pressure, and one lofexidine treated subject had a syncopal episode.
Were the decreases in MHOWS scores related to or independent of the hypotensive effects of lofexidine? Since lofexidine induced significant reductions in both sitting and standing blood pressure, the two previously mentioned effects may be inextricably related. Aside from the present study, there have been a total of six controlled studies comparing lofexidine to clonidine or to methadone (Carnwath and Hardman, 1998
; Lin et al., 1997
; Howells et al., 2002
; Bearn et al., 1996
; Gowing et al., 2002
; Bearn et al., 1998
). All of these studies were RCTs, with one being an open trial (Bearn et al., 1998
). The first study was a double-blind RCT comparing lofexidine with methadone as a detoxification agent (Bearn et al., 1996
). Results of this study indicated that lofexidine was significantly less efficacious than methadone in decreasing opioid withdrawal symptoms during days 3 to 10, but thereafter both groups showed a similar decline. Finally, there were no significant differences between lofexidine versus methadone on daily systolic or diastolic blood pressure. Another double-blind RCT comparing lofexidine with methadone (Howells et al. 2002
) found no statistical difference between the severity of withdrawal and also no difference in sitting blood pressures between lofexidine and methadone. An open study by Bearn (Bearn et al., 1998
) compared an accelerated 5-day lofexidine regimen with a 10-day lofexidine and methadone treatment for opioid withdrawal in 61 polysubstance-abusing opioid addicts. The authors of this study concluded that an accelerated 5-day lofexidine regimen attenuates withdrawal symptoms significantly more rapidly than conventional 10-day lofexidine or methadone treatment schedules. Subjects in both lofexidine groups could receive a maximum of 2.4 mg/d and there was no significant systolic or diastolic blood pressure difference between either lofexidine group. Five lofexidine subjects did experience symptoms of decreased blood pressure that resolved with dose reduction. Similar symptoms of decreased blood pressure were seen in our current study that resolved with the reduction in lofexidine dose.
The other three studies compared the efficacy and tolerability of lofexidine to clonidine, another alpha-2-adrenergic agonist. Kahn (Kahn et al., 1997
) conducted a double-blind study showing that lofexidine versus clonidine was associated with similar withdrawal symptoms from methadone. However, the overall frequency of postural hypotension was significantly lower with lofexidine than clonidine. Using a RCT, double-blind design, Carnworth (Carnworth and Hardman, 1998
) compared the degree of withdrawal in subjects detoxifying from methadone that were treated with lofexidine versus clonidine. These medications were found to be broadly equivalent on the SOWS (Short Opiate Withdrawal Scale), while lofexidine had significantly less hypotensive effects in comparison to clonidine. Finally, a third study by Lin (Lin et al., 1997
) reported on results of a randomized double-blind comparison of lofexidine (1.6 mg/day) versus clonidine (0.6 mg/day) in the treatment of heroin withdrawal. Both medications were similarly efficacious in the treatment of opioid withdrawal symptoms. In contrast, significantly more hypotensive problems were associated with clonidine than lofexidine. Thus, while indicating the broad equivalency of lofexidine versus clonidine in the treatment of withdrawal symptoms, these three studies showed the significant advantage of lofexidine versus clonidine in decreasing hypotensive effects.
These results are consistent with the overall review of this area by Gowing (Gowing et al., 2002
) in suggesting that the efficacy of lofexidine is in general comparable to that of clonidine. Direct comparisons of clonidine with lofexidine suggest that both alpha-2-adrenergic agonists are effective in reducing opioid withdrawal symptoms in humans, and that lofexidine would appear to have a slight advantage of producing a smaller hypotensive effect than clonidine. Clonidine given chronically as an antihypertensive has shown rebound hypertension upon abrupt termination and a taper is recommended. Since lofexidine is also aalpha-2-adrenergic agonist, a taper should also be considered after chronic administration to prevent the possibility of rebound hypertension. Rebound hypertension has not been demonstrated to be a problem with lofexidine detoxifications in the United Kingdom (Akhurst, 1999
Buprenorphine and lofexidine have been compared in an open-label RCT by Raistrick (Raistrick et al., 2005
). Buprenorphine was found to be at least as effective as lofexidine detoxification in 210 subjects. In an open-label comparison of lofexidine and buprenorphine (White et al., 2001
), it was found that buprenorphine subjects had a less severe withdrawal syndrome in 69 subjects.
There was good agreement between the results of lofexidine on the primary outcome measures (MHOWS) and the results on retention and the other secondary outcome measures that are frequently used by other investigators in the assessment of the potency of a medication on the alleviation of opiate withdrawal symptoms (). As shown, over the entire expanse of medication treatment days, lofexidine significantly alleviated opiate withdrawal signs as assessed by the MHOWS, the OOWS (both objective withdrawal measures), and the VAS-E (peak), which is a subjective opiate withdrawal scale. However, other subjective scales (SOWS-Gossop, SOWS-Handelsman, MCGI-Subject, and MCGI-Rater) failed to show a significant treatment difference probably indicating the lack of relative sensitivity of these tests. This broadens our findings concerning the efficacy of lofexidine in significantly decreasing MHOWS scores (an objective measure) to those of the VAS-E (a subjective measure), providing evidence of the robust efficacy of this medication in the alleviation of opiate withdrawal symptoms.
It should be noted that only 35 of the 68 randomized subjects with usable MHOWS scores were included in the primary outcome measure analyses. In addition, there was a differential loss rate for the treatment groups. With the assumption that losses were due to subjects doing poorly, the study day 5 MHOWS scores given are most likely underestimating the true scores that subjects can expect to have on day 5 (the second day of the detoxification/medication phase). The reported day 5 MHOWS scores would only apply to subjects who can be maintained on treatment until day 5. The differential loss rate, with fewer placebo subjects being retained until day 5, would indicate that the difference noted between the lofexidine and placebo groups is probably larger than indicated. Finally, the smaller than planned recruitment (68 instead of 96) and the larger than expected drop-out rate have resulted in reduced statistical power to find differences in the baseline characteristics, secondary outcome measures, safety data, and adverse events.
As previously noted, there were relatively few adverse effects (AEs) reported in this study in subjects receiving lofexidine or placebo () although the small size and the use of a p = 0.01 significance level has most likely made the detection of some adverse effects unlikely. This speaks well for the relative safety and tolerability of lofexidine when administered to heroin addicts undergoing opiate detoxification with lofexidine. As with any alpha-adrenergic agonist, physicians should be aware of the side effects including orthostatic hypotension and syncope and insure that the subject is well hydrated when lofexidine is initiated. If subjects demonstrate orthostatic changes, then the dose should be decreased.
As conceptualized by Herman (Herman et al., 1995
), there are three primary medication treatment phases for opiate addiction. These phases are 1) the short-term detoxification phase, 2) the longer-lasting opioid maintenance phase, and 3) the opioid relapse prevention therapy phase. It is the combination of detoxification, maintenance and relapse treatment that represents the ideal program of treatment for opiate addiction. However, there is a paucity of medications that are approved by the FDA for treating detoxification or relapse prevention, especially non-opioid treatments. As a detoxification agent, lofexidine would represent a considerable advance over other detoxification medications currently approved for this use (e.g. methadone and buprenorphine) because it is not a narcotic and is not considered to be an addictive drug. This would offer the opportunity for patients to safely self-medicate with lofexidine on an outpatient basis per the instructions of their physician rather than in an outpatient clinic setting.
Our study adds to the existing literature on the tolerability and efficacy of lofexidine as a detoxification agent for opioid addiction. Using an objective scale of opioid withdrawal measures (MHOWS), significant reductions in withdrawal signs were obtained with lofexidine (dose = 3.2 mg/day) versus placebo.