Myroslava K. Romach

Measurement issues in postpartum depression part 1: Anxiety as a feature of postpartum depression

SummaryWe investigated the contribution of anxiety symptoms to scores on the Edinburgh Postnatal Depression Scale (EPDS) between 36 weeks gestation and 16 weeks postpartum in 150 women. The 3-item anxiety subscale of the EPDS accounted for 47% of the total score in late pregnancy, and 38% of the total score in the postpartum period. Two categories of anxiety were common in the perinatal period: subsyndromal, situational anxiety (in particular during the last weeks of pregnancy); and clinically significant comorbid anxiety, which was experienced by nearly 50% of clinically depressed pregnant and postpartum women. The close relationship between anxiety and depression raises questions about whether symptoms of anxiety might be more common in the perinatal period than in other depressions. A strong role for anxiety symptoms in postpartum depression, and implications for its etiology and treatment, are discussed.

Mood changes during pregnancy and the postpartum period: development of a biopsychosocial model

Objective:  Women are vulnerable to mood changes during pregnancy and the postpartum period. We set out to empirically test the hypothesis that biological and psychosocial variables interact to result in this vulnerability.

Characteristics of dependent and nondependent regular users of codeine.

Although codeine is a widely used medication, the problems of codeine abuse and dependence have not been well-studied. This study characterized regular codeine users (using at least 3 days per week for 6 months, excluding those using codeine for the treatment of cancer pain) through a self-completed questionnaire. Recruitment through newspaper advertisements resulted in a total of 339 eligible questionnaires. Thirty-seven percent of subjects met DSM-IV criteria for codeine dependence. Dependent subjects (mean age, 40 +/- 10 years) were using an average of 179 (+/-171) mg of codeine per day. Codeine was predominantly used in the form of combination products with acetaminophen. Dependent subjects identified specific problems causally related to their codeine use such as depression (23%), anxiety (21%), and gastrointestinal disturbances (13%). The dependent subjects reported problems with other drugs more than did nondependent users (alcohol, 57% vs. 26%; cannabis, 23% vs. 5%; sedative/hypnotics, 33% vs. 12%; and heroin, 11% vs. 2%, respectively). Most were taking codeine primarily for a chronic pain problem (81%), although the dependent subjects currently found codeine less effective for treating pain than did the nondependent subjects and were more likely to use codeine for pleasurable effects, to relax, or to prevent withdrawal symptoms. This study showed that dependence is associated with the regular use of codeine. Pain is a key issue with these users; however, they are probably not receiving optimal treatment. There is a need to identify individuals experiencing problems with their codeine use and to develop optimal prevention and treatment strategies.

3α-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period

Allopregnanolone (ALLO) and pregnanolone (PREG), the 3α-reduced metabolites of progesterone (PROG), are potent modulators of γ-aminobutyric acid type A receptors that may function as endogenous anxiolytics. They are purported to be involved in the etiology or expression of clinical depression. In the present study we quantified ALLO and PREG, as well as PROG, 5α-dihydroprogesterone (5α-DHP), 5β-dihydroprogesterone (5β-DHP), epiallopregnanolone and pregnenolone (PREGNEN), in plasma from healthy women at five time points during pregnancy and the postpartum period. Analysis was by gas chromatography/electron capture – negative chemical ionization – mass spectrometry. Neuroactive steroids increased significantly from 10 to 36 weeks of pregnancy, except for 5β-DHP and PREGNEN which did not change significantly. PROG was the most abundant steroid throughout pregnancy, followed by 5α-DHP and ALLO. Metabolite to precursor ratios differed depending on the enzyme and substrate: the turnover of PROG to 5α-DHP (catalyzed by 5α-reductase) was stable while the conversion of PROG to 5β-DHP (catalyzed by 5β-reductase) decreased later in pregnancy. 3α-Hydroxysteroid oxidoreductase-mediated turnover of 5α- and 5β-DHP to their metabolites ALLO and PREG, respectively, rose during pregnancy, but the turnover of 5α-DHP to ALLO dropped at the late prenatal visit. At 6 weeks postpartum all steroids were significantly reduced compared with late prenatal values, with 5α-DHP being the most abundant postpartum steroid. These results provide the basis for further study of neuroactive steroids in psychiatric conditions of pregnancy and the postpartum period.

Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence

This study aimed to evaluate the concurrent and lifetime psychiatric comorbidity and drug use patterns in patients admitted to the hospital for detoxification from benzodiazepines. Psychiatric assessments using the Structured Clinical Interview for DSM-III-R with a psychosis screening module (SCID-P and II) were conducted in 30 inpatients admitted to the medical unit treatment unit of the Clinical Research and Treatment Institute of the Addiction Research Foundation for the treatment of severe benzodiazepine dependence. Patients (mean age, 36 years; range, 22-58; number of DSM-III-R criteria met for benzodiazepine substance dependence, > or = 7 out of 9 [73%], all 9 criteria [40%]) used benzodiazepines and other drugs over prolonged periods of time at high doses, and their daily functioning was substantially impaired (Mean Global Assessment of Functioning Score, 48; range, 31-60). The most common lifetime psychiatric diagnoses were major depression (33%), other psychoactive drug dependence (100%) (opioids, 77%; alcohol, 53%), and panic disorder (30%). Current psychiatric diagnoses in addition to benzodiazepine dependence included other psychoactive substance use disorders (83%) (opioids, 67%; cocaine, 13%; multiple concurrent substance use, 17%), panic disorder (13%), and generalized anxiety disorder, (20%). Personality disorders included antisocial (42%), avoidant (25%), and borderline (17%). These findings demonstrate that in patients severely dependent on benzodiazepines, additional psychoactive substance use and mental disorders are prominent. The pattern of drug use and psychiatric comorbidity differentiates these patients from therapeutic-dose benzodiazepine users.

A randomized, double‐blind, placebo‐controlled, crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a history of recreational cannabis use

This study aimed to evaluate the abuse potential and cognitive effects of nabiximols (Sativex®, GW Pharma Ltd. Salisbury, UK), an oromucosal spray primarily containing delta‐9‐tetrahydrocannabinol (THC) and cannabidiol (CBD).

Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study.

Background and Objective: Given the dual public health challenges of under-treated pain and opioid abuse, there is a need to reduce attractiveness of opioid analgesics to drug abusers. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules, indicated for treatment of chronic, moderate to severe pain, contain polymer-coated pellets of morphine, each with a core of sequestered naltrexone intended for release only upon tampering (crushing). The purpose of this study was to assess the pharmacodynamic effects (including drug-liking and euphoria) of whole and crushed ALO-01 versus morphine sulfate solution (MSS) and placebo. Methods: This was a randomized, double-blind, placebo-controlled, triple-dummy, four-way crossover study carried out at a clinical research centre. Participants were experienced non-dependent opioid users. Subjects were given either two ALO-01 60 mg capsules, crushed pellets from two ALO-01 60mg capsules, MSS 120mg or placebo; there was a 14- to 21-day washout between treatments. The primary endpoints were drug-liking visual analogue scale score, scores on items from the Addiction Research Center Inventory (ARCI) and Cole/ARCI scales characterizing abuse potential and euphoria, and pupil diameter as measured by pupillometry. Results: Morphine plasma concentrations were similar after ALO-01 crushed and MSS, with a median time to reach maximum plasma concentration (t max ) of 1.1 and 1.2 hours, respectively; the plasma naltrexone median t max was 1.1 hours after ALO-01 crushed. By comparison, the median t max for morphine with ALO-01 whole was 8.1 hours. The maximum effect (E max ) of MSS was significantly greater than placebo on pupillometry and the subjective measures (all p < 0.001). ALO-01 whole and crushed produced lower E max values and flatter effect-time profiles for subjective measures and caused less pupillary constriction than MSS. Conclusions: The results of this study demonstrated that ALO-01, whether taken orally whole as intended or tampered with by crushing and taken orally, had reduced desirability compared with MSS.

Long-term codeine use is associated with depressive symptoms.

A community survey was conducted among long-term (>6 months) users of codeine-containing products to characterize chronic use of these extensively consumed medications. Respondents recruited through newspaper advertisements completed a mailed questionnaire. Three hundred thirty-nine completed questionnaires were obtained, yielding a response rate of 70%. Codeine dependence/abuse as defined by DSM-IV criteria was present in 41% of the respondents. Two thirds of the subjects had sought help for mental health problems, most often depression (70%). Scores on the Symptom Checklist-90 subscales were modestly elevated, particularly on the Depression subscale (1.2 +/- 0.9). Long-term codeine use is strongly associated with dependence. Depression and depressive symptoms are common. These data suggest that dysphoric mood states may be significant in maintaining long-term codeine use.

Subjective Effects and Safety of Whole and Tampered Morphine Sulfate and Naltrexone Hydrochloride (ALO-01) Extended-Release Capsules versus Morphine Solution and Placebo in Experienced Non-Dependent Opioid Users

AbstractBackground and Objective: Given the dual public health challenges of under-treated pain and opioid abuse, there is a need to reduce attractiveness of opioid analgesics to drug abusers. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules, indicated for treatment of chronic, moderate to severe pain, contain polymer-coated pellets of morphine, each with a core of sequestered naltrexone intended for release only upon tampering (crushing). The purpose of this study was to assess the pharmacodynamic effects (including drug-liking and euphoria) of whole and crushed ALO-01 versus morphine sulfate solution (MSS) and placebo. Methods: This was a randomized, double-blind, placebo-controlled, triple-dummy, four-way crossover study carried out at a clinical research centre. Participants were experienced non-dependent opioid users. Subjects were given either two ALO-01 60 mg capsules, crushed pellets from two ALO-01 60 mg capsules, MSS 120 mg or placebo; there was a 14- to 21-day washout between treatments. The primary endpoints were drug-liking visual analogue scale score, scores on items from the Addiction Research Center Inventory (ARCI) and Cole/ARCI scales characterizing abuse potential and euphoria, and pupil diameter as measured by pupillometry. Results: Morphine plasma concentrations were similar after ALO-01 crushed and MSS, with a median time to reach maximum plasma concentration (tmax) of 1.1 and 1.2 hours, respectively; the plasma naltrexone median tmax was 1.1 hours after ALO-01 crushed. By comparison, the median tmax for morphine with ALO-01 whole was 8.1 hours. The maximum effect (Emax) of MSS was significantly greater than placebo on pupillometry and the subjective measures (all p < 0.001). ALO-01 whole and crushed produced lower Emax values and flatter effect-time profiles for subjective measures and caused less pupillary constriction than MSS. Conclusions: The results of this study demonstrated that ALO-01, whether taken orally whole as intended or tampered with by crushing and taken orally, had reduced desirability compared with MSS.

Update on tamper-resistant drug formulations

An expert panel convened in 2005 by the College on Problems of Drug Dependence (CPDD) to consider strategies to reduce the risk of prescription medication abuse concluded that drug formulation plays a significant role in determining risk of abuse. Efforts on the part of the pharmaceutical industry to develop drugs that deter abuse have focused primarily on opioid formulations resistant to common forms of tampering, most notably crushing or dissolving the tablet to accelerate release. Several opioid formulations developed to be tamper resistant have been approved, but the US Food and Drug Administration has not approved explicit label claims of abuse deterrence and has stated that any such claim will require substantial postmarketing data. Drug development efforts in this area raise questions about the relative impact of abuse-deterrent formulations, not only on individuals who might abuse a medication, but also on patients who are compliant with therapy. This review discusses progress since the 2005 CPDD meeting with an emphasis on opioids. Articles cited in the review were identified via a PubMed search covering the period between January 1, 2000, and October 5, 2011. Scientific work presented by the authors and their colleagues at meetings held through May 2012 also was included. Published literature suggests that development of abuse-deterrent products will require broad public health support and continued encouragement from regulatory authorities so that such products will become the expected standard of care for certain drug classes.