Antiepileptic drugs toxicity: A case of toxic epidermal necrolysis in patient with phenytoin prophylaxis post-cranial radiation for brain metastases

Background

Treatment of epilepsy with antiepileptic drugs (AED) is effective and remains the principal mode of management. A group of adverse effects and drug toxicity can develop immediately or later in the course of treatment. AEDs also have the potential of precipitating idiosyncratic adverse effects including serious cutaneous, hematological and hepatic events. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse reactions are related to or caused by a variety of medications including AEDs, they carry a high mortality and morbidity rate, accurate diagnosis and rapid treatment may improve the prognosis.

Objective

To characterize the clinical features and methods of differentiating Stevens–Johnson syndrome from toxic epidermal necrolysis using a case study and to identify other factors that may contribute to this critical illness.

Conclusion

Clinical knowledge of potential sever adverse reaction of AEDs is essential and may overcome treatment failure with major impact on health-related quality of life in people with epilepsy.     

Pharmacovigilance in children: detecting adverse drug reactions in routine electronic healthcare records. A systematic review

Aims

A systematic review of the literature published in English over 10 years was undertaken in order to describe the use of electronic healthcare data in the identification of potential adverse drug reactions (ADRs) in children.

Methods

MEDLINE and EMBASE were searched using MESH headings and text words. Titles, keywords and abstracts were checked for age <18 years, potential ADRs and electronic healthcare data. Information extracted included age, data source, pharmacovigilance method, medicines and ADRs. Studies were quality assessed.

Results

From 14 804 titles, 314 had a full text review and 71 were included in the final review. Fifty were published in North America, 10 in Scandinavia. Study size ranged from less than 1000 children to more than 10 million. Sixty per cent of studies used data from one source. Comparative observational studies were most commonly reported (66.2%) with 15% using passive surveillance. Electronic healthcare data set linkage and the quality of the data source were poorly reported. ADRs were classified using the International Classification of Disease (ICD10). Multi-system reactions were most commonly studied, followed by central nervous system and mental and behavioural disorders. Vaccines were most frequently prescribed followed by corticosteroids, general anaesthetics and antidepressants.

Conclusions

Routine electronic healthcare records were increasingly reported to be used for pharmacovigilance in children. This growing and important health protection activity could be enhanced by consistent reporting of studies to improve the identification, interpretation and generalizability of the evidence base.     

A systematic review of hospitalization resulting from medicine-related problems in adult patients

Aims

Medicine-related problems (MRPs) represent a major issue leading to hospitalization, especially in adult and elderly patients. The aims of this review are to investigate the prevalence, causes and major risk factors for MRPs leading to hospitalization in adult patients and to identify the main medicine classes involved.

Methods

Studies were identified through electronic searches of Medline, Embase, Scopus and International Pharmaceutical Abstracts between January 2000 and May 2013. A systematic review was conducted of both retrospective and prospective studies. Studies included were those involving hospitalization resulting from MRPs in adults (≥18 years old), whereas studies excluded were those investigating drug misuse and abuse and studies investigating MRPs in hospitalized patients. Data analysis was performed using SPSS version 20.

Results

Forty-five studies were identified, including 21 that investigated hospitalization resulting from adverse drug reactions, six studies that investigated hospitalization due to adverse drug events and 18 studies that investigated hospitalization due to MRPs. The median prevalence rates of hospitalization resulting from adverse drug reactions, adverse drug events and MRPs were 7% (interquartile range, 2.4–14.9%), 4.6% (interquartile range, 2.85–16.6%) and 12.1% (interquartile range, 6.43–22.2%), respectively. The major causes contributing to MRPs were adverse drug reactions and noncompliance. In addition, the major risk factors associated with MRPs were old age, polypharmacy and comorbidities. Moreover, the main classes of medicines implicated were medicines used to treat cardiovascular diseases and diabetes.

Conclusions

Hospitalization due to MRPs had a high prevalence, in the range of 4.6–12.1%. Most MRPs encountered were prevalent among adult patients taking medicines for cardiovascular diseases and diabetes.     

Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial

Aim

The disturbed circadian rhythm in haemodialysis patients results in perturbed sleep. Short term melatonin supplementation has alleviated these sleep problems. Our aim was to investigate the effects of long-term melatonin supplementation on quality of life and sleep.

Methods

In this randomized double-blind placebo-controlled trial haemodialysis patients suffering from subjective sleep problems received melatonin 3 mg day⁻¹ vs. placebo during 12 months. The primary endpoint quality of life parameter ‘vitality’ was measured with Medical Outcomes Study Short Form-36. Secondary outcomes were improvement of three sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations.

Results

Sixty-seven patients were randomized. Forty-two patients completed the trial. With melatonin, no beneficial effect on vitality was seen. Other quality of life parameters showed both advantageous and disadvantageous effects of melatonin. Considering sleep, at 3 months sleep efficiency and actual sleep time had improved with melatonin compared with placebo on haemodialysis days (difference 7.6%, 95% CI 0.77, 14.4 and 49 min, 95% CI 2.1, 95.9, respectively). At 12 months none of the sleep parameters differed significantly from placebo. Melatonin salivary concentrations at 6 months had significantly increased in the melatonin group compared with the placebo group.

Conclusions

The high drop-out rate limits the strength of our conclusions. However, although a previous study reported beneficial short term effects of melatonin on sleep in haemodialysis patients, in this long-term study the positive effects disappeared during follow up (6–12 months). Also the quality of life parameter, vitality, did not improve. Efforts should be made to elucidate the mechanism responsible for the loss of effect with chronic use.     

Information about adverse drug reactions reported in children: a qualitative review of empirical studies

AIM

To review the literature on adverse drug reactions (ADRs) in children with respect to occurrence, seriousness, type, therapeutic group, age and gender of the child and category of reporter.

METHODS

Medline and Embase databases were searched from origin and updated until February 2010. We included empirically based articles on ADRs in populations aged 0 to 17 years. Studies monitoring ADRs in patients with particular conditions or drug exposure were excluded. We extracted information about types and seriousness of ADRs, therapeutic groups, age and gender of the child and category of reporter. ADR occurrence was calculated as incidence rate and prevalence.

RESULTS

We included 33 studies monitoring ADRs in general paediatric populations. The highest numbers of ADRs were reported in national ADR databases where data were collected over a longer period than in studies monitoring inpatients and outpatients. However, prevalence and incidence were much lower in the national databases. Types of reported ADRs, seriousness of ADRs and types of medicines differed substantially between studies due to differences in time periods and patient populations. Information about ADRs was mainly provided by health care professionals, although parents also contributed reports.

CONCLUSIONS

We found a higher incidence rate of ADRs in hospitalized children and outpatients than in national databases. There seems to be considerable potential for increasing the knowledge of ADRs by advocating the submission of reports to the spontaneous reporting systems. Our study underscores that ADRs in children constitute a significant public health problem.     

Monitoring of adverse drug reactions associated with antihypertensive medicines at a university teaching hospital in New Delhi

Aim

To monitor the adverse drug reactions (ADRs) caused by antihypertensive medicines prescribed in a university teaching hospital.

Methods

The present work was an open, non-comparative, observational study conducted on hypertensive patients attending the Medicine OPD of Majeedia Hospital, Jamia Hamdard, New Delhi, India by conducting patient interviews and recording the data on ADR monitoring form as recommended by Central Drugs Standard Control Organization (CDSCO), Government of India.

Results

A total of 21 adverse drug reactions were observed in 192 hypertensive patients. Incidence of adverse drug reactions was found to be higher in patients more than 40 years in age, and females experienced more ADRs (n = 14, 7.29%) than males, 7 (3.64%). Combination therapy was associated with more number of adverse drug reactions (66.7%) as against monotherapy (33.3%). Calcium channel blockers were found to be the most frequently associated drugs with adverse drug reactions (n = 7), followed by diuretics (n = 5), and β-blockers (n = 4). Among individual drugs, amlodipine was found to be the commonest drug associated with adverse drug reactions (n = 7), followed by torasemide (n = 3). Adverse drug reactions associated with central nervous system were found to be the most frequent (42.8%) followed by musculo-skeletal complaints (23.8%) and gastro-intestinal disorders (14.3%).

Conclusions

The present pharmacovigilance study represents the adverse drug reaction profile of the antihypertensive medicines prescribed in our university teaching hospital. The above findings would be useful for physicians in rational prescribing. Calcium channel blockers were found to be the most frequently associated drugs with adverse drug reactions.     

Clinical pharmacy-led disease and medicine management programme for patients with COPD

AIM

The aim was to investigate the impact of a disease and medicine management programme, focusing on self-management in patients with chronic obstructive pulmonary disease (COPD).

METHODS

One hundred and seventy-three patients (mean age 67 years; 54% female) were recruited; 86 patients were randomly assigned to an intervention group and 87 to a usual care (control) group. Intervention patients received education on disease state, medications and breathing techniques. Patients were given booklets and a customized action plan (antibiotic and oral steroid to be initiated promptly by patients for exacerbations). Patients were followed up at 6 and 12 months during a scheduled visit. The St George''s Respiratory Questionnaire (SGRQ), COPD Knowledge and Morisky adherence questionnaires were administered to all patients at baseline, 6 and 12 months. Outcome measures included hospital admissions, emergency department (ED) visits, health-related quality of life (HRQoL) and medication adherence.

RESULTS

Over the 12-month period in the intervention group, ED visits decreased by 50% (P= 0.02) and hospitalization by approximately 60% (P= 0.01). On the SGRQ, differences reached statistical significance on the symptom (−7.5; P= 0.04) and impact (−7.4; P= 0.03) subscales but not on the physical activity subscale. There was a significant difference between the intervention and usual care groups regarding knowledge scores (75.0 vs. 59.3; P= 0.001) and good adherence to medication (77.8% vs. 60.0%, P= 0.019). There was no significant difference regarding smoking between study groups.

CONCLUSIONS

The clinical pharmacy-led management programme can improve adherence, reduce the need for hospital care in patients with COPD and improve aspects of their HRQoL.     

Prospective observational study of adverse drug reactions to diclofenac in children

AIM

The aim of this study was to investigate the type of common (occurring in >1% of patients) adverse reactions caused by diclofenac when given to children for acute pain.

METHODS

A prospective observational study was undertaken on paediatric surgical patents aged ≤12 years at Great Ormond Street and University College London Hospitals. All adverse events were recorded, and causality assessment used to judge the likelihood of them being due to diclofenac. Prospective recruitment meant not all patients were prescribed diclofenac, allowing an analysis of utilization. Causality of all serious adverse events was reviewed by an expert panel.

RESULTS

Children prescribed diclofenac were significantly older, and stayed in hospital for shorter periods than those who were not. Diclofenac was not avoided in asthmatic patients. Data on 380 children showed they suffer similar types of nonserious adverse reactions to adults. The incidence (95% confidence interval) of rash was 0.8% (0.016, 2.3); minor central nervous system disturbance 0.5% (0.06, 1.9); rectal irritation with suppositories 0.3% (0.009, 1.9); and diarrhoea 0.3% (0.007, 1.5). No serious adverse event was judged to be caused by diclofenac, meaning the incidence of serious adverse reactions to diclofenac in children is <0.8%.

CONCLUSION

Children given diclofenac for acute pain appeared to suffer similar types of adverse reactions to adults; the incidence of serious adverse reaction is <0.8%.     

Ivabradine: the evidence of its therapeutic impact in angina

Introduction:

Stable angina pectoris (SAP) is a widely prevalent disease affecting 30 000 to 40 000 per million people in Europe and the US. SAP is associated with reductions in quality of life and ability to work, and increased use of healthcare resources. Ivabradine is a drug with a unique therapeutic target, the I_f current of the sinus node, developed for the treatment of cardiovascular diseases including SAP. It has an exclusive heart rate reducing effect, without any negative effect on left ventricular function or coronary vasodilatation.

Aims:

The aim of this paper is to review the evidence concerning the use of ivabradine in the treatment of SAP.

Evidence review:

Ivabradine is an effective antianginal and antiischemic drug, not inferior to the beta blocker atenolol and the calcium channel antagonist (CCA) amlodipine. It decreases the frequency of angina attacks and increases the time to anginal symptoms during exercise. Because of its exclusive chronotropic effect, ivabradine is not associated with the typical adverse reactions associated with beta blockers or other antianginal drugs.

Clinical value:

Clinical evidence shows that ivabradine is a very good antiischemic and antianginal agent, being as effective as beta blockade and CCA therapy in controlling myocardial ischemia and symptoms of stable angina. Ongoing studies will determine the potential of ivabradine to improve morbidity and mortality in coronary artery disease and heart failure.     

Incidence of fatal adverse drug reactions: a population based study

Aims

To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.

Methods

Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.

Results

Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.

Conclusions

The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

What is already known about this subject

• Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.
• The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.
• In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.

What this study adds

• Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.
• Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.
• Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.

     

Adalimumab in ankylosing spondylitis: an evidence-based review of its place in therapy

Introduction:

Ankylosing spondylitis (AS) is an idiopathic chronic inflammatory disease that has prominent effects on the spine and peripheral joints. In addition, extraarticular manifestations such as enthesitis and acute anterior uveitis may be clinically important. In recent years, the therapy of AS has changed, largely due to the introduction of inhibitors of the proinflammatory cytokine tumor necrosis factor (TNF). Adalimumab, a human monoclonal antibody specifically for TNF, is the most recent of the TNF blocking agents that have been approved for the treatment of active, nonsteroidal antiinflammatory drug (NSAID)-refractory patients with AS.

Aims:

To evaluate the evidence for the therapeutic value of adalimumab in ankylosing spondylitis.

Evidence review:

There is clear evidence that adalimumab, administered 40 mg subcutaneously every 2 weeks, substantially improves the signs and symptoms of NSAID-refractory, active AS when compared with placebo treatment. There is ample evidence that adalimumab causes significant improvements in physical health status and overall AS-specific, health-related quality of life and physical functioning, which consequently leads to better work productivity. There is substantial evidence that adalimumab improves spinal and sacroiliac joint inflammation in AS patients. Initial results from clinical trials suggest that there is no increased risk of serious infections or malignancies in adalimumab-treated patients with AS. The most common adverse events were injection-site reactions. Limited economic evidence suggests that adalimumab 40 mg may be cost effective when used according to current valid treatment guidelines.

Place in therapy:

Adalimumab is an effective treatment for patients with active AS.     

Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase

AIM

To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents.

METHODS

Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding.

RESULTS

Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12–17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known.

CONCLUSIONS

Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.     

Factors affecting the development of adverse drug reactions (Review article)

Objectives

To discuss the effect of certain factors on the occurrence of Adverse Drug Reactions (ADRs).

Data Sources

A systematic review of the literature in the period between 1991 and 2012 was made based on PubMed, the Cochrane database of systematic reviews, EMBASE and IDIS. Key words used were: medication error, adverse drug reaction, iatrogenic disease factors, ambulatory care, primary health care, side effects and treatment hazards.

Summary

Many factors play a crucial role in the occurrence of ADRs, some of these are patient related, drug related or socially related factors. Age for instance has a very critical impact on the occurrence of ADRs, both very young and very old patients are more vulnerable to these reactions than other age groups. Alcohol intake also has a crucial impact on ADRs. Other factors are gender, race, pregnancy, breast feeding, kidney problems, liver function, drug dose and frequency and many other factors. The effect of these factors on ADRs is well documented in the medical literature. Taking these factors into consideration during medical evaluation enables medical practitioners to choose the best drug regimen.

Conclusion

Many factors affect the occurrence of ADRs. Some of these factors can be changed like smoking or alcohol intake others cannot be changed like age, presence of other diseases or genetic factors. Understanding the different effects of these factors on ADRs enables healthcare professionals to choose the most appropriate medication for that particular patient. It also helps the healthcare professionals to give the best advice to patients. Pharmacogenomics is the most recent science which emphasizes the genetic predisposition of ADRs. This innovative science provides a new perspective in dealing with the decision making process of drug selection.     

Comparing patients' and healthcare professionals' ADR reports after media attention: the broadcast of a Dutch television programme about the benefits and risks of statins as an example

AIMS

To compare adverse drug reaction (ADR) reports from patients and health professionals after the broadcast of a Dutch television consumer programme about the benefits and risks of statins.

METHODS

We performed a quantitative and qualitative analysis on patients'' and health professionals'' reports of ADRs to statins. These reports were received by the Netherlands Pharmacovigilance Centre Lareb between March 2007 and August 2007. Quantitative data consisted of patient age and gender, number of received reports and characteristics of the report (most frequently reported ADRs, seriousness, drug discontinuation and outcome of the reported reaction). Open text fields in the ADR reporting form were categorized and a content analysis was carried out.

RESULTS

Media attention led to a peak in patient reporting of ADRs but not in reporting by health professionals. There were no differences between patient and health professional reports in seriousness of the ADRs and drug cessation. Patients reported nonrecovery more often than health professionals. The TV programme is mentioned as a reason for drug discontinuation in almost 30 reports. Patients often felt that they did not receive sufficient information and that their concerns were not adequately addressed by healthcare professionals.

CONCLUSIONS

Media attention affects drug use and ADR reporting by patients. Patient reports can provide additional information, making them a useful source of information next to health professional reports. Content analysis provides vital insights into the impact of statins on daily life, and patients'' concerns about adverse reactions should be recognized in reports to national pharmacovigilance centres.     

A Randomized Placebo-Controlled Trial of Targeted Prefrontal Cortex Modulation with Bilateral tDCS in Patients with Crack-Cocaine Dependence

Background:

Transcranial direct current stimulation over the dorsolateral prefrontal cortex has been shown to be clinically useful in the treatment of drug addiction.

Methods:

We conducted a double-blind randomized clinical trial aiming to assess the effects of bilateral dorsolateral prefrontal cortex transcranial direct current stimulation (left cathodal/right anodal) on crack-cocaine addiction. We defined craving as the primary outcome, and other clinical measurements, including depressive and anxiety symtoms, and quality of life, as secondary outcomes. Seventeen male crack-cocaine users (mean age 30.4±9.8 SD) were randomized to receive 5 sessions of active transcranial direct current stimulation (2 mA, 35cm², for 20 minutes), every other day, and 19 males (mean age 30.3±8.4 SD) to receive sham-transcranial direct current stimulation (placebo) as control group.

Results:

Craving scores were significantly reduced in the transcranial direct current stimulation group after treatment when compared with sham-transcranial direct current stimulation (P=.028) and baseline values (P=.003), and decreased linearly over 4 weeks (before, during, and after treatment) in the transcranial direct current stimulation group only (P=.047). Changes of anxiety scores towards increase in the sham-transcranial direct current stimulation and decrease in the transcranial direct current stimulation group (P=.03), and of the overall perception of quality of life (P=.031) and of health (P=.048) towards decrease in the sham-transcranial direct current stimulation group and increase in the transcranial direct current stimulation group differed significantly between groups.

Conclusions:

Repetitive bilateral transcranial direct current stimulation over the dorsolateral prefrontal cortex reduced craving for crack-cocaine use, decreased anxiety, and improved quality of life. We hypothesize that transcranial direct current stimulation effects may be associated with increased prefrontal processing and regulation of craving behavior.     

Trends of reporting of 'serious'vs. 'non-serious' adverse drug reactions over time: a study in the French PharmacoVigilance Database

AIM

To investigate trends in spontaneous reporting to the French Pharmacovigilance system of ‘serious’ (SADRs) and ‘non-serious’ (NSADRs) adverse drug reactions over time.

METHODS

Annual SADR : NSADR ratios were calculated for each drug and their evolution tested with linear trend tests.

RESULTS

Among the 39 new active substances commercialized in France in 2000, 16 had sufficient data to perform linear trend tests. An increasing linear relation was found for five widely prescribed drugs, a non-significant increasing trend for eight others, i.e. drugs mostly used in hospitals.

CONCLUSION

ADR reports mainly concern NSADRs during first years of marketing. Reports of SADRs are proportionally more frequent later.     

Preceptor Perceptions of Pharmacy Student Team Quality Assurance Projects

Objectives

To assess preceptors'' opinions of the impact of quality assurance projects.

Methods

Students were given the opportunity to directly apply material learned in class in a “real world” environment by completing a quality assurance project in a community or health-system pharmacy. All preceptors (n = 38) were contacted via telephone and given the opportunity to respond to open-ended questions concerning their experience with student-team quality assurance projects.

Results

Preceptors indicated the quality assurance projects benefited their practice sites by providing additional resources (53%, n = 19), decreased medication errors (22%, n = 8), and increased awareness of the importance of quality assurance (22%, n = 8). Ninety-four percent of respondents (n = 34) perceived the projects had a positive impact on patient care and 92% (n = 33) perceived a positive impact on themselves.

Conclusions

Preceptors felt that quality assurance projects performed by pharmacy-student teams were beneficial to patient care, the practice site, and themselves. The quality assurance projects have broad applications and can be added to a medication safety class or to the introductory pharmacy practice experience (IPPE) sequence.     

Dosing and Monitoring of Methadone in Pregnancy: Literature Review

Background:

The pharmacokinetics of methadone is altered during pregnancy, but the most appropriate dosing and monitoring regimen has yet to be identified.

Objective:

To review dosing and monitoring of methadone therapy in pregnancy.

Methods:

A literature search was performed in several databases (PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews) from inception to May 2012. The search terms were “methadone”, “pregnancy”, “pharmacokinetic”, “clearance”, “metabolism”, “therapeutic drug monitoring”, and “methadone dosing”. Additional papers were identified by searching the bibliographies of primary and review articles. All English-language primary articles related to methadone pharmacokinetics in pregnancy were included. Articles not related to maternal outcomes were excluded.

Results:

The literature search yielded 1 case report and 10 studies discussing use of methadone by pregnant women. Methadone pharmacokinetics in pregnancy has been studied in 3 pharmacokinetic trials, and split dosing of methadone in pregnant women has been described in 1 case report and 3 dosing trials. Only 4 trials evaluated monitoring of methadone concentration in pregnancy. The studies included in this review confirm that methadone pharmacokinetics is altered in pregnancy and is potentially correlated with increases in maternal withdrawal symptoms. Insufficient evidence is available to warrant routine monitoring of serum methadone concentrations in pregnant women with opioid dependence.

Conclusions:

Few studies of methadone pharmacokinetics and therapeutic drug monitoring are available for pregnant women with opioid dependence. Although it is known that methadone pharmacokinetics is altered in pregnancy, there is insufficient evidence to guide dosage adjustments and serum concentration monitoring. Until further studies are available, regular follow-up of maternal withdrawal symptoms and empiric dosage adjustments throughout pregnancy are still recommended.