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Terapi farmakologi untuk pengurusan ketagihan opium

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Background

Pharmacologic therapies for management of heroin withdrawal have been studied and reviewed widely. Opium dependence is generally associated with less severe dependence and milder withdrawal symptoms than heroin. The evidence on withdrawal management of heroin might therefore not be exactly applicable for opium.

Objectives

To assess the effectiveness and safety of various pharmacologic therapies for the management of the acute phase of opium withdrawal.

Search methods

We searched the following sources up to September 2017: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, regional and national databases (IMEMR, Iranmedex, and IranPsych), main electronic sources of ongoing trials, and reference lists of all relevant papers. In addition, we contacted known investigators to obtain missing data or incomplete trials.

Selection criteria

Controlled clinical trials and randomised controlled trials on pharmacological therapies, compared with no intervention, placebo, other pharmacologic treatments, different doses of the same drug, and psychosocial intervention, to manage acute withdrawal from opium in a maximum duration of 30 days.

Data collection and analysis

We used the standard methodological procedures expected by Cochrane.

Main results

We included 13 trials involving 1096 participants. No pooled analysis was possible. Studies were carried out in three countries, Iran, India, and Thailand, in outpatient and inpatient settings. The quality of the evidence was generally very low.

When the mean of withdrawal symptoms was provided for several days, we mainly focused on day 3. The reason for this was that the highest severity of opium withdrawal is in the second to fourth day.

Comparing different pharmacological treatments with each other, clonidine was twice as good as methadone for completion of treatment (risk ratio (RR) 2.01, 95% confidence interval (CI) 1.69 to 2.38; 361 participants, 1 study, low‐quality evidence). All the other results showed no differences between the considered drugs: baclofen versus clonidine (RR 1.06, 95% CI 0.63 to 1.80; 66 participants, 1 study, very low‐quality evidence); clonidine versus clonidine plus amantadine (RR 1.03, 95% CI 0.86 to 1.24; 69 participants, 1 study); clonidine versus buprenorphine in an inpatient setting (RR 1.04, 95% CI 0.90 to 1.20; 1 study, 35 participants, very low‐quality evidence); methadone versus tramadol (RR 0.95, 95% CI 0.65 to 1.37; 1 study, 72 participants, very low‐quality evidence); methadone versus methadone plus gabapentin (RR 1.17, 95% CI 0.96 to 1.43; 1 study, 40 participants, low‐quality evidence), and tincture of opium versus methadone (1 study, 74 participants, low‐quality evidence).

Comparing different pharmacological treatments with each other, adding amantadine to clonidine decreased withdrawal scores rated at day 3 (mean difference (MD) ‐3.56, 95% CI ‐5.97 to ‐1.15; 1 study, 60 participants, very low‐quality evidence). Comparing clonidine with buprenorphine in an inpatient setting, we found no difference in withdrawal symptoms rated by a physician (MD ‐1.40, 95% CI ‐2.93 to 0.13; 1 study, 34 participants, very low‐quality evidence), and results in favour of buprenorpine when rated by participants (MD ‐11.80, 95% CI ‐15.56 to ‐8.04). Buprenorphine was superior to clonidine in controlling severe withdrawal symptoms in an outpatient setting (RR 0.35, 95% CI 0.19 to 0.64; 1 study, 76 participants). We found no difference in the comparison of methadone versus tramadol (MD 0.04, 95% CI ‐2.68 to 2.76; 1 study, 72 participants) and in the comparison of methadone versus methadone plus gabapentin (MD ‐2.20, 95% CI ‐6.72 to 2.32; 1 study, 40 participants).

Comparing clonidine versus buprenorphine in an outpatient setting, more adverse effects were reported in the clonidine group (1 study, 76 participants). Higher numbers of participants in the clonidine group experienced hypotension at days 5 to 8, headache at days 1 to 8, sedation at days 5 to 8, dizziness and dry mouth at days 1 to 10, and nausea at days 1 to 9. Sweating was reported in a significantly higher number of participants in the buprenorphine group at days 1 to 10. We found no difference between groups for all the other comparisons considering this outcome.

Comparing different dosages of the same pharmacological detoxification treatment, a high dose of clonidine (1 to 1.2 mg/day) did not differ from a low dose of clonidine (0.5 to 0.6 mg/day) in completion of treatment in an inpatient setting (RR 1.00, 95% CI 0.84 to 1.19; 1 study, 68 participants), however a higher number of participants with hypotension was reported in the high‐dose group (RR 3.25, 95% CI 1.77 to 5.98). Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low‐quality evidence).

Authors' conclusions

Results did not support using any specific pharmacological approach for the management of opium withdrawal due to generally very low‐quality evidence and small or no differences between treatments. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium. All of the assessed medications might be useful in alleviating symptoms. Those who receive clonidine might experience hypotension.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Ubat untuk pengurusan ketagihan opium

Apakah tujuan ulasan ini?

Tujuan ulasan Cochrane ini adalah untuk mengetahui ubat mana yang lebih berkesan dan selamat untuk pengurusan ketagihan opium. Kami mengumpul dan menganalisa semua kajian yang relevan untuk menjawab soalan ini dan menjumpai 13 kajian yang melibatkan 1096 peserta.

Mesej utama

Ulasan ini menyertakan 12 perbandingan berikut: baclofen berbanding clonidine, clonidine berbanding clonidine tambah amantadine, clonidine berbanding buprenorphine, clonidine berdos tinggi berbanding clonidine berdos rendah berbanding pengurusan bersimptom, clonidine berbanding methadone, methadone berbanding tramadol, methadone berbanding methadone tambah gabapentin, pengurangan beransur methadone berbanding penarikan tiba‐tiba methadone, methadone tambah amitriptyline berbanding methadone, diphenoxylate berbanding propoxyphene, tiga protokol berbeza tinktur opium, dan tinktur opium berbanding methadone. Kajian tersebut dijalankan di tiga negara, Iran, India dan Thailand. Sokongan daripada satu syarikat farmasikutikal dalam bentuk pembekalan percuma ubatan dilaporkan hanya dalam satu kajian.

Bukti adalah tidak jelas sama ada sebarang penilaian ubatan adalah lebih berkesan daripada yang lain dalam pengurusan ketagihan opium. Namun, ia kelihatan bahawa simptom ketagihan opium adalah signifikan dalam beberapa hari selepas pemberhentian opium. Semua ubatan yang dinilai mungkin berguna dalam melegakan simptom. Penggunaan clonidine mungkin menyebabkan tekanan darah rendah.

Apakah yang dikaji dalam ulasan ini?

Simptom ketagihan opium adalah sama seperti untuk opioid yang lain seperti heroin, tetapi dengan intensiti ringan. Pesakit lazim memerlukan ubatan untuk membantu melegakan simptom ketagihan.

Apakah keputusan utama ulasan ini?

Kami tidak pasti sama ada kesan clonidine berbeza daripada yang dibawa oleh baclofen dalam bilangan peserta yang melengkapkan rawatan (kepastian bukti adalah sangat rendah).

Kami tidak pasti sama ada penambahan amantadine kepada clonidine mengurangkan keseriusan simptom ketagihan dalam hari 1 kepada 3 dalam persekitaran pesakit dalam, atau sama ada ia mempunyai kesan atas pelengkapan rawatan (kepastian bukti adalah sangat rendah).

Kami tidak pasti sama ada buprenorphine adalah lebih bagus daripada clonidine dalam pengawalan simptom ketagihan dalam persekitaran pesakit dalam dan pesakit luar (kepastian bukti adalah sangat rendah). Kesan sampingan, termasuk tekanan darah rendah, dilaporkan dalam bilangan yang lebih banyak dalam kumpulan clonidine.

Kami tidak pasti sama ada dos tinggi clonidine berbeza daripada dos rendah clonidine dalam pelengkapan rawatan dalam persekitaran pesakit dalam (kepastian bukti sangat rendah), namun bilangan kes tekanan darah rendah yang lebih tinggi dilaporkan dengan clonidine berdos tinggi.

Clonidine mungkin lebih bagus daripada methadone dalam mengekalkan pesakit dalam rawatan di dalam persekitaran pesakit luar.

Kami tidak pasti sama ada tramadol berbeza daripada methadone dalam pelengkapan rawatan dan dalam melegakan simptom penarikan, dan sama ada kesan sampingan adalah biasa dengan methadone (kepastian bukti sangat rendah).

Penambahan gabapentin kepada methadone mungkin membawa sedikit atau tiada perbezaan dalam pelengkapan rawatan dan dalam keseriusan simptom ketagihan.

Kami tidak pasti sama ada penarikan methadone secara tiba‐tiba berkait dengan aduan pesakit yang lebih kurang sama daripada pengurangan methadone beransur (kepastian bukti sangat rendah).

Tinktur opium mungkin membawa tiada perbezaan dalam pelengkapan rawatan, keseriusan simptom penarikan, dan kesan sampingan dalam perbandingan kepada methadone.

Setakat manakah ulasan ini dikemaskini?

Kami telah mencari kajian‐kajian yang diterbitkan sehingga September 2017.

Authors' conclusions

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Implications for practice

Due to generally very low‐quality evidence and small or no differences between treatments, we could make no definitive conclusions regarding the use of any specific pharmacological approach for the management of opium withdrawal. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium, and patients need pharmacologic assistance for passing through the detoxification process.

The trials included in this study were carried out in a variety of inpatient and outpatient settings. Completion of treatment in the inpatient settings was generally high. However, this benefit should be weighed with the expenses of inpatient management. Withdrawal management is safe and can be provided in outpatient settings as well. However, since withdrawal management does not equate with treatment of dependence, long‐term care is necessary to prevent a return to opium use.

Implications for research

This review showed that little is known about the withdrawal management of opium with specific medications. There is a need for well‐designed, well‐reported studies assessing alpha2 adrenergic agonists, buprenorphine, methadone, and tincture of opium. More specifically, further studies comparing clonidine with buprenorphine might be helpful in determining the effectiveness of these medications on detoxification from opium. Since withdrawal from opium is less severe than from heroin, many patients might be effectively managed in outpatient settings with less cost. Carrying out trials in outpatient settings will therefore increase the utilisation of the results in general practice.

Most of the included studies had serious risks of biases. Future studies should apply appropriate randomisation methods with adequate allocation concealment. For all dropped‐out cases, the reasons and time of dropping out, as well as the group to which each case belonged, should be provided. The number of participants who have been assessed in each arm should be provided for all measures. It is recommended that published and well‐studied questionnaires or checklists be used for the assessment of withdrawal symptoms and that a total score in predetermined times for each person be calculated and the mean withdrawal score for those in each intervention arm be provided. Providing the scores in addition to graphs will increase the utility of data in future reviews. The most frequently assessed days in the studies are days 3, 5, and 7, and providing data for these days will allow comparisons of results between studies. Peak withdrawal score is also a good measure that makes it possible to compare interventions with different durations. Carrying out urine tests for opium is recommended as an appropriate outcome measure for assessing successful completion of withdrawal management. Adverse effects should also be reported specifically for each intervention arm to allow for a safety comparison. It is also recommended that in studies in which individuals with dependence to a variety of opioids are included, the results be provided separately for each type of opioid.

Summary of findings

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Summary of findings for the main comparison. Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

Patient or population: management of opium withdrawal
Setting: outpatient and inpatient
Intervention: pharmacological detoxification treatment
Comparison: other pharmacological detoxification treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with other pharmacological detoxification treatment

Risk with pharmacological detoxification treatment

Completion of treatment:

baclofen versus clonidine

Study population

RR 1.06
(0.63 to 1.80)

66
(1 CCT)

⊕⊝⊝⊝
VERY LOW 1 2

441 per 1000

468 per 1000
(278 to 794)

Completion of treatment: clonidine versus clonidine plus amantadine, inpatient setting

Study population

RR 1.03
(0.86 to 1.24)

69
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 3

857 per 1000

883 per 1000
(737 to 1000)

Completion of treatment: clonidine versus buprenorphine, inpatient setting

Study population

RR 1.04
(0.90 to 1.20)

35
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 4

952 per 1000

990 per 1000
(857 to 1000)

Completion of treatment: clonidine versus methadone

Study population

RR 2.01
(1.69 to 2.38)

361
(1 CCT)

⊕⊕⊝⊝
LOW 5

415 per 1000

834 per 1000
(701 to 988)

Completion of treatment: methadone versus tramadol

Study population

RR 0.95
(0.65 to 1.37)

72
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 6

629 per 1000

597 per 1000
(409 to 861)

Completion of treatment: methadone versus methadone plus gabapentin

Study population

RR 1.17
(0.96 to 1.43)

40
(1 RCT)

⊕⊕⊝⊝
LOW 2

850 per 1000

994 per 1000
(816 to 1000)

Completion of treatment: tincture of opium versus methadone

Study population

RR 1.00
(0.95 to 1.05)

74
(1 RCT)

⊕⊕⊝⊝
LOW 2

1000 per 1000

1000 per 1000
(950 to 1000)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded one level for risk of bias: high risk of selection, performance, and detection bias; unclear risk of attrition bias.
2Downgraded two levels for imprecision: one study with very few participants.
3Downgraded one level for risk of bias: high risk of performance and detection bias; unclear risk of selection bias.
4Downgraded one level for risk of bias: high risk of reporting bias; unclear risk of selection bias.
5Downgraded one level for risk of bias: high risk of performance, detection, attrition, and reporting bias; unclear risk of selection bias.
6Downgraded one level for risk of bias: high risk of reporting bias; unclear risk of selection and attrition bias.

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Summary of findings 2. Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

Patient or population: management of opium withdrawal
Setting: outpatient and inpatient
Intervention: pharmacological detoxification treatment
Comparison: other pharmacological detoxification treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with other pharmacological detoxification treatment

Risk with pharmacological detoxification treatment

Withdrawal symptoms at day 3: clonidine versus clonidine plus amantadine, inpatient setting

The mean withdrawal symptoms at day 3: clonidine versus clonidine plus amantadine was 9.83 days.

MD 3.56 days lower
(5.97 lower to 1.15 lower)

60
(1 CCT)

⊕⊝⊝⊝
VERY LOW 1 2

Withdrawal symptoms at day 3: clonidine versus buprenorphine,inpatient setting

The mean withdrawal symptoms at day 3: clonidine versus buprenorphine in inpatient setting was 12.5 days.

MD 1.4 days lower
(2.93 lower to 0.13 higher)

34
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 3

Withdrawal symptoms at day 3: methadone versus tramadol

The mean withdrawal symptoms at day 3: methadone versus tramadol was 8.5 days.

MD 0.04 days higher
(2.68 lower to 2.76 higher)

72
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 4

Withdrawal symptoms at day 3: methadone versus methadone plus gabapentin

The mean withdrawal symptoms at day 3: methadone versus methadone plus gabapentin was 13.4 days.

MD 2.2 days lower
(6.72 lower to 2.32 higher)

40
(1 RCT)

⊕⊕⊝⊝
LOW 2

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded one level for risk of bias: high risk of performance and detection bias; unclear risk of selection bias.
2Downgraded two levels for imprecision: one study with very few participants.
3Downgraded one level for risk of bias: high risk of reporting bias; unclear risk of selection bias.
4Downgraded one level for risk of bias: high risk of reporting bias; unclear risk of selection and attrition bias.

Background

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Description of the condition

Opioid dependence is a major health and social issue in most societies, but access and cultural attitudes affect the patterns of opioid use among different countries. Opium is used for pleasure, as a painkiller, a hypnotic, and for the treatment of premature ejaculation (Ahmadi 2004). In opium‐cultivating countries and some of their neighbours, opium use is more common than use of other opioids. This is particularly true in Afghanistan, Laos, Myanmar, and Iran (UNODC 2011). Opium has traditionally been used in Pakistan, India, China, Thailand, Bangladesh, Nepal, Sri Lanka, Turkey, Iraq, Jordan, Egypt, Bahrain, Oman, and Kuwait, as well (Ray 2006; WHO/EMRO 2004). In some of these countries, such as in Iran, opium has always been the most widely abused illicit drug. A national survey on epidemiology of drug use in Iran showed that among the adult male population, 8.9% and 3% were current opium users and opium dependents, respectively (Iranian MoH 2002). A new national household survey from Iran also showed that opium is the main substance that leads to substance use disorders (Amin‐Esmaeili 2016). A systematic review on drug use in Iranian universities reported that the prevalence of opium use ranged from 7.1% to 10.2%, and that the daily use ranged from 3.4% to 8.8% among  male students. The rates were much lower in female students (Rahimi‐Movaghar 2006). Another new systematic review reported opium abuse to be 4% in college and high school students (Menati 2016). A drug use survey in Afghanistan in 2005 reported the existence of about 150,000 regular opium users (0.6% of the total population) in that country (Afghanistan Counter Narcotics & UNODC 2005); in four years, this number increased to 230,000 (UNODC 2010). In India, the National Household Survey on Drug Abuse in 2002 reported that 0.5% of adult males were current (use within last month) opium users, and that there were about 1.4 million opium users in that country (Ray 2004). Another household survey in the state of Arunachal Pradesh in India showed that 6.6% of individuals aged 15 years or older were current opium users (Chaturvedi 2013). In many countries, the pattern of drug use has shifted from softer opioids to harder ones like heroin in the last decade; however, there are at least 5 million regular opium users in the world.

Opium is obtained from the unripe seed capsules of the poppy plant, Papaver somniferum. The milky juice is dried and powdered to make powdered opium, which contains a number of alkaloids. These alkaloids can be divided into two distinct chemical classes, phenanthrenes and benzylisoquinolines. The principal phenanthrenes are morphine (10% of opium), codeine (0.5%), and thebaine (0.2%). The principal benzylisoquinolines are papaverine (1%) and noscapine (6%) (Brunton 2006).  

Opium has the properties of opioid analgesics. Its analgesic and sedative actions are due mainly to its content of morphine. However, opium acts less rapidly than morphine, since opium appears to be more slowly absorbed. The relaxing action of the papaverine and noscapine on intestinal muscle makes it more constipating than morphine. Alkaloids of opium have their own mechanisms of action. Papaverine has a direct relaxant effect on smooth muscle and causes gastrointestinal disturbance. Noscapine is a centrally acting cough suppressant. Codeine is also used for cough suppression (Sweetman 2007). Thebaine acts like strychnine, and may produce convulsions (PubChem 2008; Yamazoe 1981).

Diamorphine hydrochloride (heroin) is an acetylated morphine derivative and is a more potent opioid analgesic than morphine. Diamorphine is much more lipid‐soluble and has a more rapid onset and shorter duration of action than morphine. Although deacetylation to morphine occurs rapidly in the blood, it occurs only slowly in the cerebral spinal fluid following intraspinal injection of diamorphine (Sweetman 2007).

Currently, opium continues to be consumed by traditional means, that is eating and smoking. Although in most cases opium is used occasionally and mainly in male gatherings, regular use of opium occurs and causes dependence (Ray 2006). Opium dependence is less debilitating than heroin dependence. Opium users have a more stable lifestyle than heroin users. A high proportion of opium users are married and live with their families (Jafari 2010; Razaghi 1999). Psychiatric comorbidity is significantly less in opium users than in heroin users (Ghaffarnejad 2009). Opium dependence is not a benign disorder; however, in comparison to heroin, opium costs less, requires fewer doses per day, and has a less toxic withdrawal (Westermeyer 1977).

Cessation of opium use in an individual who is opium dependent gives rise to a classical opiate withdrawal syndrome of mild intensity. The signs and symptoms of the syndrome include irritability, anxiety, apprehension, muscular and abdominal pains, chills, nausea, diarrhoea, yawning, lacrimation, sweating, sneezing, rhinorrhoea, general weakness, and insomnia. The acute physical signs of withdrawal syndrome usually stop after 14 days, but, as happens for heroin dependence, protracted syndrome that includes reduced well‐being, malaise, and periodic strong cravings may continue for months. Completion of withdrawal and remaining abstinent is difficult for most opium dependents. Although relapse rate after completion of withdrawal is high, withdrawal remains a required first step for many forms of longer‐term treatment (World Health Organization 2009). As opium is a less abusive and less harmful substance than heroin, and individuals with opium dependence generally have a higher socioeconomic status and less degree of psychopathology, in practice many of those with opium dependence are provided withdrawal management when referred for treatment.

Description of the intervention

Limited information is currently available on the management of opium withdrawal. Several pharmacological modalities of detoxification including alpha2 adrenergic agonists, buprenorphine, reducing dose of methadone, opioid antagonists (with minimal sedation or under heavy sedation), and symptomatic medication, with or without psychosocial treatment, have been used for opiate dependence, most of them focused on heroin users (Amato 2013; Gowing 2009a; Gowing 2009b; Gowing 2010; Gowing 2014).

Why it is important to do this review

There are no clear guidelines on how to treat individuals dependent on opium (Zarghami 2008). All guidelines for management of opioid dependence are based on evidence for managing heroin‐dependent patients, which constitute the main population of opioid dependents in Western countries. However, people dependent on opium appear to differ in several ways from those who use heroin. Opium has different pharmacokinetics, adverse effects, and severity of withdrawal. In addition, modes of administration of opium and socio‐demographic characteristics of users are also different from heroin. Consequently, managing opium dependence based on evidence on management of heroin dependence is the subject of debate.

Objectives

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To assess the effectiveness and safety of various pharmacological therapies for the management of the acute phase of opium withdrawal.

Methods

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Criteria for considering studies for this review

Types of studies

Randomised controlled trials and controlled clinical trials on pharmacological detoxification treatments to manage acute withdrawal from opium. The trials should have provided detailed information on the type and dose of pharmacological therapies, and have listed at least one major outcome measure.

Types of participants

Opium‐dependent individuals who underwent acute withdrawal management.

Trials including participants with additional physical or psychological illness were also eligible, and there was no restriction on setting.

Types of interventions

Experimental intervention

Pharmacological detoxification treatments, including alpha2 adrenergic agonists, buprenorphine taper, methadone taper, opioid antagonists with minimal sedation, opioid antagonists under heavy sedation, taper of tincture of opium, and other pharmacologic treatments.

Control or comparison interventions

  • Placebo

  • No intervention

  • Other pharmacological interventions alone or in combination with any psychosocial intervention

  • Different dosages of the same drug for management of acute opium withdrawal

  • Any psychosocial intervention

We excluded studies comparing the same pharmacologic treatment administered in different settings. We also excluded studies comparing different protocols for anaesthesia in ultrarapid opioid detoxification.

Types of outcome measures

Primary outcomes

  1. Completion of treatment, as number of participants completing the detoxification programme

  2. Use of opium at the end of the detoxification programme, as number of participants with positive urinalysis or number of participants having gone through naloxone challenge test or who have started naltrexone

  3. Duration and severity of signs and symptoms of withdrawal, including patient self rating

  4. Nature, incidence, and course of adverse effects

  5. Mortality rate

We differentiated withdrawal signs and symptoms from adverse effects of treatment exactly as defined in each included study.

When the mean of withdrawal symptoms was provided for several days, we presented all results in the analysis section, and mainly focused on day 3 in the text. The reason for this is that opium withdrawal is most severe in the second to fourth day.

Secondary outcomes

  1. Client satisfaction

  2. Use of other abusive substances

  3. Fatal or non‐fatal overdose rate

  4. Relapse rate at follow‐up

Search methods for identification of studies

We undertook both electronic and manual searches to identify eligible studies. There was no language restriction.

Electronic searches

We searched the following international bibliographic databases:

  • the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 9) in the Cochrane Library;

  • MEDLINE via Ovid (1966 to 13 September 2017);

  • Embase via Embase.com (1974 to 13 September 2017);

  • CINAHL (Cumulative Index to Nursing and Allied Health Literature) via EBSCOhost (1982 to 11 September 2017);

  • PsycINFO via Ovid (1887 to 11 September 2017).

We also searched the following regional and national bibliographic databases:

  • IMEMR (Index Medicus for WHO Eastern Mediterranean) (1984 to 13 September 2017);

  • Iranmedex (up to 13 September 2017);

  • IranPsych (up to 17 March 2012; the database has not been updated since March 2012).

We searched the following trials registries:

  • ClinicalTrials.gov (clinicaltrials.gov) (searched 13 September 2017);

  • World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp) (searched 13 September 2017);

  • CenterWatch Clinical Trials Listing Service (www.centerwatch.com) (searched 22 September 2017);

  • ISRCTN registry (www.isrctn.com) (searched 13 September 2017).

Searching other resources

We also searched conference proceedings likely to contain trials relevant to the review and the reference lists of all relevant papers to identify further studies.

We contacted the authors of retrieved studies for missing data or incomplete trials. The full search strategies for all databases, as well as the numbers of retrieved records, are included in Appendix 1.

Data collection and analysis

Selection of studies

Two review authors (MAE, JG) inspected the reports identified by the search by reading titles and abstracts. Any disagreements were resolved through discussion with third review author (ARM). We obtained the full texts of those studies deemed potentially relevant, and two review authors (ARM, JG) assessed these for inclusion in the review. Any disagreements were resolved by discussion. The process of study selection, including the numbers of retrieved and selected documents, is presented in the flowchart according to a modified PRISMA statement (Figure 1).


Study flow diagram.

Study flow diagram.

Data extraction and management

Two review authors (MAE, JG) independently extracted data using a data extraction form. Any disagreements were resolved through discussion with a third review author (ARM). As the included studies assessed different comparisons, we did not perform meta‐analysis and summarised the key findings narratively.

We intended to extract the following data if provided in each included study.

  • Study characteristics:

    • Author and year of publication

    • City and country

    • Study implementation year

    • Funding

  • Methods:

    • Study design

    • Setting and sites

    • Number of arms (groups)

    • Sequence generation

    • Allocation concealment

    • Blinding of participants/therapists/assessors

    • Comparability of participants in all arms

    • Intention‐to‐treat analysis

    • Instruments administered to assess study outcomes

    • The person who assessed study outcomes

  • Participants:

    • Eligibility criteria

    • Number of participants in each arm at baseline

    • Sex

    • Age (range, mean and standard deviation)

    • Comorbidities

    • Other drugs used

  • Interventions:

    • Main pharmacologic interventions in each arm

    • Details of pharmacologic interventions (dose, frequency, duration)

    • Other interventions

    • Adherence

  • Outcomes:

    • Number who completed treatment

    • Negative urinalysis for morphine at the end of detoxification programme

    • Severity of withdrawal (mean withdrawal score or number of participants who complained of each withdrawal symptom) in different days of detoxification process

    • Severity of craving (mean craving score)

    • Drug adverse effects

    • Client satisfaction

    • Use of other abusive substances

    • Mortality rate

    • Fatal and non‐fatal overdose rate

    • Negative urinalysis for morphine in follow‐up

Assessment of risk of bias in included studies

Two review authors (JG, ARM) independently assessed the risk of bias of the included studies using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreements were resolved by discussion The recommended approach for assessing risk of bias in studies included in a Cochrane Review is a two‐part tool, addressing seven specific domains, namely sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other sources of bias. The first part of the tool involves describing what was reported to have occurred in the study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry, in terms of low, high or unclear risk. We used the criteria indicated by the Cochrane Handbook for Systematic Reviews of Interventions adapted to the addiction field to make these judgements. See Appendix 2 for details.

The domains of sequence generation and allocation concealment (avoidance of selection bias) were addressed in the tool by a single entry for each study.

We considered blinding of participants, personnel, and outcome assessment (avoidance of performance bias and detection bias) separately for objective outcomes (e.g. dropout) and subjective outcomes (e.g. duration and severity of signs and symptoms of withdrawal, adverse effects).

We considered incomplete outcome data (avoidance of attrition bias) for all outcomes except for drop out from treatment, which is frequently the primary outcome measure in trials on addiction.

Measures of treatment effect

We presented dichotomous outcomes (e.g. number of participants who completed treatment) as risk ratios (RR). We presented continuous outcomes (e.g. severity of withdrawal) as mean differences (MD). We expressed uncertainties in the results with 95% confidence intervals (CI).

When the mean of withdrawal symptoms was provided for several days, we presented all results in the analysis section, and mainly focused on day 3 in the text. The reason for this is that withdrawal from opium is most severe in the second to fourth day.

Data synthesis

Where possible, we had planned to combine the outcomes from the individual trials through meta‐analysis (comparability of intervention and outcomes between trials) using a random‐effects model, as we expected a certain degree of heterogeneity among trials. However, meta‐analysis was not possible due to substantial differences between interventions in the studies. We reported results of the included studies individually for each trial, re‐expressed as RR for dichotomous outcomes and MD for continuous outcomes with 95% CI. We presented the results using Review Manager 5 (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

We would have assessed statistical heterogeneity using the I2 statistic and the Chi2 test (x2) (Higgins 2011). In addition, we intended to consider factors such as setting and duration of treatment as confounders, taking these into account in the analysis wherever possible. However, we did not perform sensitivity analysis due to heterogeneity among interventions and comparisons.

'Summary of findings' table

We assessed the overall quality of the evidence for the primary outcome using the GRADE system (GRADE 2004; Guyatt 2008; Guyatt 2011; Schünemann 2006), which takes into account issues not only related to internal validity but also to external validity, such as directness of results. The 'Summary of findings' tables present the main findings of a review in a transparent and simple tabular format. In particular, they provide key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the main outcomes.

The GRADE system uses the following criteria for assigning grades of evidence.

  • High: We are very confident that the true effect lies close to that of the estimate of the effect.

  • Moderate: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

  • Low: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

  • Very low: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Grading is decreased for the following reasons.

  • Serious (‐1) or very serious (‐2) study limitation for risk of bias.

  • Serious (‐1) or very serious (‐2) inconsistency between study results.

  • Some (‐1) or major (‐2) uncertainty about directness (the correspondence between the population, the intervention, or the outcomes measured in the studies actually found and those under consideration in our systematic review).

  • Serious (‐1) or very serious (‐2) imprecision of the pooled estimate.

  • Strong suspicion of publication bias (‐1).

Results

Description of studies

Results of the search

The search identified 1624 records through international bibliographic databases, 1919 through regional and national bibliographic databases, 90 through electronic sources of ongoing trials, and 216 through other sources. Five hundred and nine out of 1624 studies identified from the international databases were duplicates and were removed. In total, we screened 3340 records and excluded 3212 after our review of titles and abstracts for inclusion criteria. From the remaining 128 records, we excluded 108 studies (109 articles) after our review of the full texts. Another five studies are awaiting classification due to unavailability of the full text or inability to contact authors to inquire about the types of opioids used by participants. Finally, 13 clinical trials (from 14 articles) were considered to be eligible for the review and were included. The flow diagram of steps of the searches and the results is presented in Figure 1.

Included studies

The 13 included studies involved 1096 participants. Only two studies were randomised controlled trials (Kheirabadi 2008; Tabassomi 2016); the other studies were evaluated as controlled clinical trials. See Characteristics of included studies.

Interventions

The included studies considered 12 different comparisons.

  1. Baclofen versus clonidine (1 study, 66 participants) (Ahmadi Abhari 2003).

  2. Clonidine versus clonidine plus amantadine (1 study, 69 participants) (Amiri 2014).

  3. Clonidine versus buprenorphine (2 studies, 111 participants) (Salehi 2007a; Ziaaddini 2012).

  4. High‐dose clonidine versus low‐dose clonidine versus symptomatic management (1 study, 102 participants) (Satija 1988).

  5. Clonidine versus methadone (1 study, 361 participants) (Taraghi 2005).

  6. Methadone versus tramadol (1 study reported in 2 papers, 72 participants) (Salehi 2007b).

  7. Methadone versus methadone plus gabapentin (1 study, 40 participants) (Kheirabadi 2008).

  8. Gradual reduction of methadone versus sudden withdrawal (1 study, 20 participants) (Lal 1976).

  9. Methadone plus amitriptyline versus methadone (1 study, 44 participants) (Salehi 2005).

  10. Diphenoxylate versus propoxyphene (1 study, 105 participants) (Singh 1984).

  11. Three different protocols of tincture of opium (1 study, 32 participants) (Somogyi 2008).

  12. Tincture of opium versus methadone (1 study, 74 participants) (Tabassomi 2016).

Clonidine and methadone were used in six trials, and buprenorphine and tincture of opium in two trials. Maximum doses of clonidine were 0.2 to 1.2 mg/day, and maximum doses of methadone were 10 to 65 mg/day. Baclofen, tramadol, amitriptyline, gabapentin, diphenoxylate, and propoxyphene were used in one trial each. Three studies assessed different dosage or tapering mechanism for a medication, namely for clonidine, methadone, and tincture of opium.

One study had three arms (Satija 1988), comparing high‐dose clonidine versus low‐dose clonidine versus symptomatic treatment; we analysed the comparison between the first two arms. Another study claimed to have four arms (Singh 1984), however it actually consisted of two trials in different time frames: diphenoxylate and propoxyphene were compared in one study in high doses and in another study in low doses. The remaining 11 studies had two arms.

In 12 studies, all participants were opium dependent. In one study with 66 participants (Ahmadi Abhari 2003), 90% were opium dependent; however, separate data for the opium dependents were not available. We decided to include the study and use the data for the all 66 participants.

For a more detailed description of studies, see Characteristics of included studies.

Participants

The studies included 1096 participants, of whom only 14 (from 4 studies) were female. One study did not report the gender of the participants (Taraghi 2005). Age range was from 18 to 70 years. One study only reported that participants were required to be under 40 (Salehi 2007a). The mean age of the total samples ranged from 25.5, in Ziaaddini 2012, to 41, in Lal 1976. Five studies provided the average amount of daily opium use in participants, which ranged from 4.8, in Singh 1984 and Taraghi 2005, to 78, in Somogyi 2008. One study required that participants use less than 2 g of opium per day (Salehi 2007a).

Settings and duration of trials

Six and five trials used outpatient and inpatient settings, respectively. Two studies did not report the setting used. The duration of detoxification programmes was 3 to 15 days in inpatient settings and 3 to 25 days in outpatient settings. The 13 studies were carried out in three countries: Iran (nine studies), India (three studies), and Thailand (one study). Six studies did not report the enrolment dates. The other studies reported enrolment dates from 1980 to 2013. Ten studies were published after 2002, and three other studies (from India) were published before 1989.

Outcomes

The included studies reported the following outcomes.

  1. Number of participants completing treatment (8 studies).

  2. Withdrawal scores (13 studies), using a variety of scales. The total mean withdrawal scores were provided in six studies.

  3. Adverse effects (8 studies).

  4. Mortality rate (3 studies).

The included studies used the following measures for assessing withdrawal signs and symptoms.

  1. Short Opioid Withdrawal Scale, 10‐item, subjective measure (Ahmadi Abhari 2003; Salehi 2005).

  2. Clinical Opioid Withdrawal Scale (COWS), 11 symptoms, include both subjective and objective measures (Amiri 2014; Ziaaddini 2012).

  3. Subjective Opiate Withdrawal Scale, 16‐item (Kheirabadi 2008; Salehi 2007b).

  4. Methadone Symptoms Checklist, 16‐item, subjective measure (Somogyi 2008).

  5. Withdrawal Symptoms Rating Scale, 24‐item, objective measure (Satija 1988).

  6. Adjective Rating Withdrawal Scale (ARWS), 16‐item, subjective measure (Ziaaddini 2012).

  7. Mental symptoms checklist, 5‐item, subjective measure (Ahmadi Abhari 2003; Salehi 2005; Salehi 2007b).

  8. Objective Opioid Withdrawal Scale (OOWS), 13‐item, objective measure (Tabassomi 2016).

Types of comparisons

We grouped the studies into two main comparisons.

  1. Pharmacological detoxification treatments versus other pharmacological detoxification interventions.

  2. Pharmacological detoxification treatments versus different dosages of the same drug.

Within the two comparisons, we compared each type of pharmacological intervention.

Excluded studies

We excluded a total of 108 studies (from 109 articles). Some studies had more than one reason for exclusion. Reasons for exclusion were as follows.

  • Participants not dependent on opium (85 studies).

  • Types of opioids were not reported (3 studies).

  • Not a controlled trial (18 studies).

  • Anaesthesia procedures (5 studies).

  • Not on the management of withdrawal symptoms within the first 30 days after stoppage of opium use (5 studies).

  • Same pharmacologic interventions were provided in all arms (3 studies).

  • No results on outcome measures provided (1 study).

  • Participants were not dependent on opioids (1 study).

  • Opium users were included, however despite contacting the authors, we were unable to obtain separate data for opium users (6 studies).

Risk of bias in included studies

See Figure 2 and Figure 3.


Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation

Of the 13 included studies, only two reported a random sequence generation method and were considered as at low risk of bias (Kheirabadi 2008; Tabassomi 2016). We judged six studies as being at unclear risk of bias because they did not provide sufficient information about method of sequence generation (Amiri 2014; Lal 1976; Salehi 2007b; Satija 1988; Taraghi 2005; Ziaaddini 2012). We judged five studies as being at high risk of bias (Ahmadi Abhari 2003; Salehi 2005; Salehi 2007a; Singh 1984; Somogyi 2008): Ahmadi Abhari 2003 and Salehi 2007a used alternate assignment; Salehi 2005 reported assignment based on the order of presentation; and Somogyi 2008 reported allocation depending on participants’ self reported prior opium use.

Allocation concealment

Of the 13 included studies, only two reported allocation concealment and were considered as at low risk of bias (Kheirabadi 2008; Tabassomi 2016). We judged six studies as being at unclear risk of bias because they did not provide sufficient information about allocation concealment method (Amiri 2014; Lal 1976; Salehi 2007b; Satija 1988; Taraghi 2005; Ziaaddini 2012). We judged five studies in which allocation concealment was not done as being at high risk of bias (Ahmadi Abhari 2003; Salehi 2005; Salehi 2007a; Singh 1984; Somogyi 2008).

Blinding

Performance bias for objective outcomes

Seven studies provided detailed information about blinding of participants and personnel and were considered as at low risk of bias for this domain (Kheirabadi 2008; Lal 1976; Salehi 2005; Salehi 2007a; Salehi 2007b; Tabassomi 2016; Ziaaddini 2012). Singh 1984 did not assess any objective outcomes. We judged the remaining five studies as at high risk of bias: four studies were not blinded (Ahmadi Abhari 2003; Amiri 2014; Somogyi 2008; Taraghi 2005), and Satija 1988 stated that the drugs were given in identical capsules and that participants and the evaluating doctor were blinded, but we judged that blinding was impossible because of symptomatic therapy in one of the study groups.

Performance bias for subjective outcomes

Seven studies provided detailed information about blinding of participants and personnel and were considered as at low risk of bias for this domain (Kheirabadi 2008; Lal 1976; Salehi 2005; Salehi 2007a; Salehi 2007b; Tabassomi 2016; Ziaaddini 2012). We judged the remaining six studies to be at high risk of bias: four studies were not blinded (Ahmadi Abhari 2003; Amiri 2014; Somogyi 2008; Taraghi 2005); Satija 1988 stated that the drugs were given in identical capsules and that participants and the evaluating doctor were blinded, but we judged that blinding was impossible because of symptomatic therapy in one of the study groups; and in Singh 1984 blinding of participants was done for the type of medication but not for the dose of medications.

Detection bias for objective outcomes

Six studies provided detailed information about blinding of outcome assessors and were considered as being at low risk of bias for this domain (Kheirabadi 2008; Salehi 2005; Salehi 2007a; Salehi 2007b; Tabassomi 2016; Ziaaddini 2012). Singh 1984 did not assess any objective outcomes. In four studies, either blinding of outcome assessment was not done (Ahmadi Abhari 2003; Amiri 2014; Taraghi 2005), or the provided information was insufficient (Lal 1976); however, for assessment of the main objective outcome (completion of treatment), it is unlikely that the assessment was affected by lack of blinding of the assessors. In the two remaining studies (Satija 1988; Somogyi 2008), blinding of outcome assessment was not done, and vital signs were assessed as objective outcomes, therefore we considered these two studies to be at high risk of detection bias.

Detection bias for subjective outcomes

Six studies provided detailed information about blinding of outcome assessors and were considered as being at low risk of bias for this domain (Kheirabadi 2008; Salehi 2005; Salehi 2007a; Salehi 2007b; Tabassomi 2016; Ziaaddini 2012). We judged Lal 1976 as at unclear risk of bias because they did not provide sufficient information on blinding of outcome assessment. In six studies blinding of outcome assessors was not done (Ahmadi Abhari 2003; Amiri 2014; Satija 1988; Singh 1984; Somogyi 2008; Taraghi 2005), therefore assessment of subjective outcomes, such as subjective withdrawal symptoms and adverse effects, was prone to high risk of bias.

Incomplete outcome data

We considered incomplete outcome data for all outcomes except completion of treatment (or dropout). Of the 13 studies, we judged six as being at low risk of attrition bias (Amiri 2014; Kheirabadi 2008; Lal 1976; Satija 1988; Tabassomi 2016; Ziaaddini 2012). In Amiri 2014, the two study groups were reported to have nearly equal non‐compliance and loss to follow‐up cases (i.e. 5 out of 35 (14.3%) in the clonidine group versus 4 of 34 (11.8%) in the clonidine plus amantadine group). Kheirabadi 2008 reported 3 of 20 excluded participants (15%) in the placebo group and none in the gabapentin group, which is unlikely to result in biased estimates. Lal 1976 and Tabassomi 2016 had no missing data. Satija 1988 reported that an equal number of participants dropped out in the three groups (4 of 34 in each group (11.8%)); Ziaaddini 2012 reported that only 1 of 21 participants (4.8%) in the clonidine group and none of 14 participants in the buprenorphine group discontinued treatment. There was insufficient information in three studies (Ahmadi Abhari 2003; Salehi 2005; Salehi 2007b), which we considered as at unclear risk of bias. We judged the remaining four studies to be at high risk of bias (Salehi 2007a; Singh 1984; Somogyi 2008; Taraghi 2005). Salehi 2007a reported 13 dropouts from a total of 89 participants (14.6%), of which 4 were due to hypotension (group not reported), and 7 in the clonidine group versus 2 in the buprenorphine group were due to losses to follow‐up and may have induced bias in effect estimates. Singh 1984 reported 15 dropouts of 105 participants (14.3%), and Somogyi 2008 reported 13 dropouts of 45 participants (28.9%), but their groups were not reported. Taraghi 2005 reported 20 dropouts of 120 participants (16.7%) in the clonidine group and 141 dropouts of 241 participants (58.5%) in the methadone group, but some key outcomes like adverse effects were reported only in those who completed treatment.

Selective reporting

In eight studies (Ahmadi Abhari 2003; Amiri 2014; Kheirabadi 2008; Lal 1976; Salehi 2007b; Satija 1988; Tabassomi 2016; Taraghi 2005), the outcomes presented in the results section were consistent with those specified in the methods section. Amiri 2014 was registered in the Iranian Clinical Trials Registry, and the presented outcomes were consistent with the registered protocol. We considered five studies as being at high risk of reporting bias (Salehi 2005; Salehi 2007a; Singh 1984; Somogyi 2008; Ziaaddini 2012). Salehi 2005 did not report completion rate of treatment in the 25 days, and mean of total withdrawal score at days 7, 15, 17, and 25. Salehi 2007a, Singh 1984, and Somogyi 2008 did not report completion rate. In Ziaaddini 2012, the rate of positive urinary samples for opioids at the end of six months was reported as one of the main outcomes of the study, but the results are not presented, and there is no report about side effects.

In addition, there were reporting errors in two studies (Salehi 2007b; Taraghi 2005). In Salehi 2007b, the difference between the two groups in mean mental score at day 15 is reported as significant, but as obtained from the results tables it is insignificant. There are several reporting errors in Taraghi 2005: for example, the rates presented for patient satisfaction in each group are not matched with the reported significance of difference (P value).

Six studies did not report source of funding. In the remaining studies, academic institutions were mainly reported as the source of funding. Only one study mentioned funding from a pharmaceutical company (Singh 1984), for which two companies had provided the two compared medications.

Effects of interventions

See: Summary of findings for the main comparison Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal; Summary of findings 2 Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

As the included trials investigated outcomes of different comparisons, it was not possible to perform meta‐analysis.

Primary outcomes

Comparison 1: Pharmacological detoxification treatments versus other pharmacological detoxification interventions
1.1 Completion of treatment

See summary of findings Table for the main comparison.

1.1.1 Baclofen versus clonidine

One study involving 66 participants found no difference between groups (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.63 to 1.80; very low‐quality evidence) (Ahmadi Abhari 2003).

1.1.2 Clonidine versus clonidine plus amantadine

One study involving 69 participants found no difference between groups (RR 1.03, 95% CI 0.86 to 1.24; very low‐quality evidence) (Amiri 2014).

1.1.3 Clonidine versus buprenorphine in an inpatient setting

One study involving 35 participants found no difference between groups (RR 1.04, 95% CI 0.90 to 1.20; very low‐quality evidence) (Ziaaddini 2012).

1.1.4 Clonidine versus methadone

One study involving 361 participants found that people taking clonidine were twice as likely to complete treatment as those taking methadone (RR 2.01, 95% CI 1.69 to 2.38; low‐quality evidence) (Taraghi 2005).

1.1.5 Methadone versus tramadol

One study involving 72 participants found no difference between groups (RR 0.95, 95% CI 0.65 to 1.37; very low‐quality evidence) (Salehi 2007b).

1.1.6 Methadone versus methadone plus gabapentin

One study involving 40 participants found no difference between groups (RR 1.17, 95% CI 0.96 to 1.43; low‐quality evidence) (Kheirabadi 2008).

1.1.7 Tincture of opium versus methadone

One study involving 74 participants found that all participants completed treatment in both groups (RR 1.00, 95% CI 0.95 to 1.05; low‐quality evidence) (Tabassomi 2016).

For all see Analysis 1.1.

1.2 Duration and severity of signs and symptoms of withdrawal at day 3 of treatment

See summary of findings Table 2.

1.2.1 Clonidine versus clonidine plus amantadine

One study involving 60 participants found that adding amantadine to clonidine decreased withdrawal scores rated at day 3 (mean difference (MD) ‐3.56, 95% CI ‐5.97 to ‐1.15; very low‐quality evidence) (Amiri 2014).

1.2.2 Clonidine versus buprenorphine in an inpatient setting

One study involving 34 participants found no difference between groups using the Clinical Opiate Withdrawal Scale at day 3, rated by a psychiatrist (MD ‐1.40, 95% CI ‐2.93 to 0.13). Furthermore, this study found results in favour of buprenorphine using the Adjective Rating Withdrawal Scale at day 3, rated by participants (MD ‐11.80, 95% CI ‐15.56 to ‐8.04; very low‐quality evidence) (Ziaaddini 2012).

1.2.3. Clonidine versus buprenorphine in an outpatient setting

One study involving 76 participants found that a smaller number of participants experienced severe withdrawal symptoms in the buprenorphine group at day 3 (RR 0.35, 95% 0.19 to 0.64; very low‐quality evidence) (Salehi 2007a).

1.2.4 Methadone versus tramadol

One study involving 72 participants found no difference between groups using mean withdrawal score at day 3 (MD 0.04, 95% CI ‐2.68 to 2.76). In addition, the difference in mean mental withdrawal score at day 3 did not differ between groups (MD ‐0.23, 95% CI ‐2.10 to 1.64; very low‐quality evidence) (Salehi 2007b).

1.2.5 Methadone versus methadone plus gabapentin

One study involving 40 participants found no difference between groups at day 3 (MD ‐2.20, 95% CI ‐6.72 to 2.32; low‐quality evidence) (Kheirabadi 2008).

For all see Analysis 1.2.

Comparing baclofen versus clonidine, one study involving 66 participants found no difference between groups at days 0, 1, 2, 3, 4, 7, and 14 (results provided only by graphs) (Ahmadi Abhari 2003).

Comparing clonidine versus methadone, one study involving 361 participants assessed the severity of 10 withdrawal symptoms and found that dysphoria, agitation, irritability, muscle aches, yawning, and hot flashes were more severe in the clonidine group (Taraghi 2005). However, the time and number of assessments were not reported.

Comparing methadone plus amitriptyline versus methadone, one study involving 44 opium participants found no difference between groups in mean withdrawal score; lower mental withdrawal scores at days 7 and 25 in the amitriptyline group, but not at days 15 and 17; and lower scores on the McGill Pain Questionnaire at days 15, 17, and 25 in the amitriptyline group, but not at day 7 (Salehi 2005).

One study with 105 participants involved four groups: low‐dose diphenoxylate, low‐dose propoxyphene, high‐dose diphenoxylate, and high‐dose propoxyphene (Singh 1984). Comparing low doses of diphenoxylate and propoxyphene, insomnia and diarrhoea were significantly lower in the diphenoxylate group. The study found no differences between these groups with regard to other withdrawal symptoms. Comparing high doses of diphenoxylate and propoxyphene, the study found no difference in the number of participants with each of eight withdrawal symptoms. Although there was no randomisation process between low and high dose of each medication, the authors concluded that symptoms were lower in the high‐dose regimen than in the low‐dose regimen.

Use of opium at the end of detoxification programme: number of participants with positive urinalysis, or number of participants to have gone through naloxone challenge test or to have started naltrexone

Only one study involving 35 participants, comparing clonidine versus buprenorphine in an inpatient setting, reported data on participants staying in naltrexone treatment at 6 months, showing no difference between groups (RR 1.50, 95% CI 0.80 to 2.82) (Ziaaddini 2012).

Adverse effects

Comparing baclofen versus clonidine, one study involving 66 participants assessed severity of adverse effects at days 0, 1, 2, 3, 4, 7, and 14, and showed no difference between groups (only graphs were provided) (Ahmadi Abhari 2003). Only two adverse effects, euphoria (46.7% in the baclofen group versus 0% in the clonidine group, P < 0.01) and vomiting (33% in the baclofen group versus 0% in the clonidine group, P < 0.05) were significantly more frequent in the baclofen group.

Comparing clonidine versus buprenorphine in an outpatient setting, one study involving 76 participants reported that 4 participants dropped out due to hypotension, but it is not specified to which group they were allocated, and these four cases have been removed from analysis (Salehi 2007a). In the 76 participants that remained in treatment, hypotension, headache, sedation, dizziness, dry mouth, nausea, constipation, and sweating were assessed and reported every day from day 1 to day 10. More adverse effects were reported in the clonidine group. Significantly higher numbers of participants in the clonidine group experienced hypotension at days 5 to 8, headache at days 1 to 8, sedation at days 5 to 8, dizziness and dry mouth at days 1 to 10, and nausea at days 1 to 9. Sweating was reported in a significantly higher number of participants in the buprenorphine group at days 1 to 10.

Comparing clonidine versus buprenorphine in an inpatient setting, one study involving 35 participants did not report adverse effects (Ziaaddini 2012), stating only that one participant in the clonidine group left the study before completion, on the second day due to blood pressure below 90/60 mmHg.

Comparing methadone versus tramadol, one study involving 72 participants reported no difference between groups for side effect scores on day 7 (Salehi 2007b). On day 14, participants in the methadone group had significantly more drowsiness (P = 0.0195) and sweating (P = 0.003) than those in tramadol group (very low‐quality evidence).

Comparing tincture of opium versus methadone, one study involving 74 participants found no difference between groups in the incidence of all nine adverse effects evaluated (headache, dizziness, sleepiness, misbalance, constipation, nausea, perspiration, tension, and respiratory depression) (Tabassomi 2016).

Comparing diphenoxylate versus propoxyphene, one study involving 105 participants reported no adverse effects with low‐dose regimens (Singh 1984); one participant on high‐dose diphenoxylate reported constipation, and two participants on high‐dose propoxyphene reported mild giddiness.

Mortality rate

No deaths were reported in the included studies.

Comparison 2: Pharmacological detoxification treatments versus different dosages of the same drug
Completion of treatment

Comparing high‐dose clonidine versus low‐dose clonidine, one study involving 68 participants found no difference between the two groups for completion of treatment (RR 1.00, 95% CI 0.84 to 1.19) (Satija 1988).

Comparing gradual reduction of methadone versus sudden withdrawal of methadone, one study involving 20 participants reported that all participants were retained for 15 days in treatment, although completion of treatment was not reported as an outcome measure (Lal 1976).

Withdrawal symptoms

Comparing gradual reduction of methadone versus sudden withdrawal of methadone, one study involving 20 participants reported that the number of participants complaining of withdrawal symptoms during treatment was higher in the "gradual reduction" group than in the "stable dose and sudden withdrawal" group (RR 2.25, 95% CI 1.02 to 4.94) (Lal 1976). The number of participants with body aches and pain, insomnia, rhinorrhoea, diarrhoea, nervousness and tremor was higher in the "gradual reduction" group. In addition, symptoms were reported to be more severe and tended to persist throughout the period of withdrawal in the "gradual reduction" group.

Adverse effects

Comparing high‐dose clonidine versus low‐dose clonidine, one study involving 60 participants reported that more participants experienced hypotension in the high‐dose group (RR 3.25, 95% CI 1.77 to 5.98), however no definition was provided for hypotension and no participant required specific therapy to treat hypotension (Satija 1988).

Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low‐quality evidence), (Lal 1976).

Comparing three different protocols of tincture of opium, one study involving 45 participants reported no significant adverse effects in all three groups (Somogyi 2008).

Mortality rate

No deaths were reported in the included studies.

No useful data were provided for all the other primary outcomes.

Secondary outcomes

We intended to extract and present data for our secondary outcomes as well, however only one study, 35 participants, reported results at six‐month follow‐up, and showed no significant difference between groups (RR 1.50, 95% CI 0.80 to 2.82; very low‐quality evidence) (Ziaaddini 2012).

No other reliable data on the secondary outcomes were provided in the included studies.

Discussion

available in

Summary of main results

Regular use of opium can lead to physical and psychological dependence. Opium dependence imposes a considerable burden on societies, being associated with decreased productivity, family problems, crime, and increased healthcare costs. It is important to use specific evidence for management of opium dependence and to understand to what degree the evidence for treatment of heroin dependence applies to opium dependence as well.

In most Asian countries, detoxification is more accessible and affordable than maintenance treatment. Another review on maintenance treatment of opium was inconclusive regarding the effective maintenance management of opium dependence (Rahimi‐Movaghar 2013).

We included 13 trials involving 1096 participants in this review. The 13 trials evaluated 12 different comparisons, and no pooled analysis was possible. Studies were carried out in three countries, Iran (nine studies), India (three studies), and Thailand (one study). Six studies were conducted in outpatient settings and five in inpatient settings. In two studies the setting was not described. The quality of the evidence was generally very low.

In the five studies carried out in inpatient settings, the reported completion rate ranged from 86% to 100%. In the five studies carried out in outpatient settings and assessing this outcome, completion rate ranged from 41% to 100%. No case of mortality was reported in the 13 included studies (although most studies did not mention that there were no deaths). These results show an overall promise with withdrawal management of opium.

In the single comparisons, we found low‐quality evidence that clonidine was better than methadone for number of participants completing treatment. We found no difference between groups for this outcome for any of the other comparisons. Regarding withdrawal symptoms, adding amantadine to clonidine decreased withdrawal scores at days 1 to 3, and buprenorphine was superior to clonidine in controlling severe withdrawal symptoms in the first week in an outpatient setting. We found no differences for all the other comparisons.

Regarding adverse effects, more adverse effects were reported with clonidine when compared with buprenorphine in an outpatient setting, in particular a higher number of participants with hypotension was reported with high‐dose clonidine.

No analysis was possible for three comparisons, since only graphs or P values were provided in the papers. These comparisons were diphenoxylate versus propoxyphene, three different protocols of opium tincture, and the addition of amitriptyline to methadone.

Overall completeness and applicability of evidence

We intended to answer the question regarding the most effective interventions for management of opium withdrawal. However, based on this review we were unable to answer this question. This review presented 12 different comparisons, the evidence for which was generally of very low quality. The included studies were carried out mainly in Iran, with a few in India and Thailand. Four of the 13 included studies were published in the Persian language. Specifically, Iran is a country with a high rate of opium use and a high number of publications on opioids (Rahimi‐Movaghar 2015). The included studies suffer for low internal validity. In terms of external validity, it should be noted that the included studies involved 1096 participants, who were from the part of the world with the highest prevalence of opium use and dependence. However, women were underepresented in the study population, and an inpatient setting was used in many of the studies, which in the actual world is not the case, as most opium dependents go through detoxification in outpatient settings. All studies assessed severity of withdrawal symptoms during treatment, but with different scales. Other main outcomes such as completion of treatment and adverse effects were not assessed in all studies. Other objective outcomes, such as urinalysis for morphine and naloxone challenge test at the end of detoxification, were rarely investigated.

Quality of the evidence

Our GRADE assessment of the quality of the evidence of the included studies was very low. The major flaws in the studies were risk of selection, performance, detection, attrition, and reporting bias. In addition, sample size was very small in all of the included studies, therefore the results were highly imprecise.

Potential biases in the review process

We contacted study authors to request unpublished data and were able to obtain significant data for this review.

Agreements and disagreements with other studies or reviews

Two previous systematic reviews assessed similar comparisons in opioid‐dependent individuals:

  1. Gowing 2009a compared buprenorphine with clonidine for management of opioid withdrawal (10 studies) and found that buprenorphine was superior than clonidine in controlling withdrawal symptoms, which was similar to our findings. However, we included one study with very low‐quality evidence reporting no difference between groups in completion rate of opium dependents in an inpatient setting, which differed from the findings of Gowing 2009a;

  2. Gowing 2014 compared methadone and clonidine for management of opioid withdrawal (9 studies, 659 participants) and found no difference between groups in completion rate. However, we found low‐quality evidence from one study that completion rate in opium dependents was higher with clonidine than with tapering doses of methadone.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Comparison 1 Pharmacological detoxification treatment versus other pharmacological detoxification treatment, Outcome 1 Completion of treatment.
Figures and Tables -
Analysis 1.1

Comparison 1 Pharmacological detoxification treatment versus other pharmacological detoxification treatment, Outcome 1 Completion of treatment.

Comparison 1 Pharmacological detoxification treatment versus other pharmacological detoxification treatment, Outcome 2 Withdrawal symptoms at day 3.
Figures and Tables -
Analysis 1.2

Comparison 1 Pharmacological detoxification treatment versus other pharmacological detoxification treatment, Outcome 2 Withdrawal symptoms at day 3.

Summary of findings for the main comparison. Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

Patient or population: management of opium withdrawal
Setting: outpatient and inpatient
Intervention: pharmacological detoxification treatment
Comparison: other pharmacological detoxification treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with other pharmacological detoxification treatment

Risk with pharmacological detoxification treatment

Completion of treatment:

baclofen versus clonidine

Study population

RR 1.06
(0.63 to 1.80)

66
(1 CCT)

⊕⊝⊝⊝
VERY LOW 1 2

441 per 1000

468 per 1000
(278 to 794)

Completion of treatment: clonidine versus clonidine plus amantadine, inpatient setting

Study population

RR 1.03
(0.86 to 1.24)

69
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 3

857 per 1000

883 per 1000
(737 to 1000)

Completion of treatment: clonidine versus buprenorphine, inpatient setting

Study population

RR 1.04
(0.90 to 1.20)

35
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 4

952 per 1000

990 per 1000
(857 to 1000)

Completion of treatment: clonidine versus methadone

Study population

RR 2.01
(1.69 to 2.38)

361
(1 CCT)

⊕⊕⊝⊝
LOW 5

415 per 1000

834 per 1000
(701 to 988)

Completion of treatment: methadone versus tramadol

Study population

RR 0.95
(0.65 to 1.37)

72
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 6

629 per 1000

597 per 1000
(409 to 861)

Completion of treatment: methadone versus methadone plus gabapentin

Study population

RR 1.17
(0.96 to 1.43)

40
(1 RCT)

⊕⊕⊝⊝
LOW 2

850 per 1000

994 per 1000
(816 to 1000)

Completion of treatment: tincture of opium versus methadone

Study population

RR 1.00
(0.95 to 1.05)

74
(1 RCT)

⊕⊕⊝⊝
LOW 2

1000 per 1000

1000 per 1000
(950 to 1000)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded one level for risk of bias: high risk of selection, performance, and detection bias; unclear risk of attrition bias.
2Downgraded two levels for imprecision: one study with very few participants.
3Downgraded one level for risk of bias: high risk of performance and detection bias; unclear risk of selection bias.
4Downgraded one level for risk of bias: high risk of reporting bias; unclear risk of selection bias.
5Downgraded one level for risk of bias: high risk of performance, detection, attrition, and reporting bias; unclear risk of selection bias.
6Downgraded one level for risk of bias: high risk of reporting bias; unclear risk of selection and attrition bias.

Figures and Tables -
Summary of findings for the main comparison. Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal
Summary of findings 2. Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal

Patient or population: management of opium withdrawal
Setting: outpatient and inpatient
Intervention: pharmacological detoxification treatment
Comparison: other pharmacological detoxification treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with other pharmacological detoxification treatment

Risk with pharmacological detoxification treatment

Withdrawal symptoms at day 3: clonidine versus clonidine plus amantadine, inpatient setting

The mean withdrawal symptoms at day 3: clonidine versus clonidine plus amantadine was 9.83 days.

MD 3.56 days lower
(5.97 lower to 1.15 lower)

60
(1 CCT)

⊕⊝⊝⊝
VERY LOW 1 2

Withdrawal symptoms at day 3: clonidine versus buprenorphine,inpatient setting

The mean withdrawal symptoms at day 3: clonidine versus buprenorphine in inpatient setting was 12.5 days.

MD 1.4 days lower
(2.93 lower to 0.13 higher)

34
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 3

Withdrawal symptoms at day 3: methadone versus tramadol

The mean withdrawal symptoms at day 3: methadone versus tramadol was 8.5 days.

MD 0.04 days higher
(2.68 lower to 2.76 higher)

72
(1 CCT)

⊕⊝⊝⊝
VERY LOW 2 4

Withdrawal symptoms at day 3: methadone versus methadone plus gabapentin

The mean withdrawal symptoms at day 3: methadone versus methadone plus gabapentin was 13.4 days.

MD 2.2 days lower
(6.72 lower to 2.32 higher)

40
(1 RCT)

⊕⊕⊝⊝
LOW 2

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded one level for risk of bias: high risk of performance and detection bias; unclear risk of selection bias.
2Downgraded two levels for imprecision: one study with very few participants.
3Downgraded one level for risk of bias: high risk of reporting bias; unclear risk of selection bias.
4Downgraded one level for risk of bias: high risk of reporting bias; unclear risk of selection and attrition bias.

Figures and Tables -
Summary of findings 2. Pharmacological detoxification treatment compared to other pharmacological detoxification treatment for management of opium withdrawal
Comparison 1. Pharmacological detoxification treatment versus other pharmacological detoxification treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Completion of treatment Show forest plot

7

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Baclofen versus clonidine

1

66

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [0.63, 1.80]

1.2 Clonidine versus clonidine plus amantadine

1

69

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.86, 1.24]

1.3 Clonidine versus buprenorphine, inpatient setting

1

35

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.90, 1.20]

1.4 Clonidine versus methadone

1

361

Risk Ratio (M‐H, Fixed, 95% CI)

2.01 [1.69, 2.38]

1.5 Methadone versus tramadol

1

72

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.65, 1.37]

1.6 Methadone versus methadone plus gabapentin

1

40

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.96, 1.43]

1.7 Tincture of opium versus methadone

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.95, 1.05]

2 Withdrawal symptoms at day 3 Show forest plot

4

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

2.1 Clonidine versus clonidine plus amantadine

1

60

Mean Difference (IV, Fixed, 95% CI)

‐3.56 [‐5.97, ‐1.15]

2.2 Clonidine versus buprenorphine, inpatient setting

1

34

Mean Difference (IV, Fixed, 95% CI)

‐1.40 [‐2.93, 0.13]

2.3 Methadone versus tramadol

1

72

Mean Difference (IV, Fixed, 95% CI)

0.04 [‐2.68, 2.76]

2.4 Methadone versus methadone plus gabapentin

1

40

Mean Difference (IV, Fixed, 95% CI)

‐2.20 [‐6.72, 2.32]

Figures and Tables -
Comparison 1. Pharmacological detoxification treatment versus other pharmacological detoxification treatment