Effects of sedative-hypnotics on sleep quality among patients with insomnia: evidence from an observational, pre-post study in India

Insomnia continues to be overlooked despite its association with life threatening comorbidities like cardiovascular diseases and diabetes. Addressing the deleterious effects of insomnia poses a challenging task, especially in India, considering patients’ attitude about the disease and the suboptimal healthcare system [1]. A recent report claimed that over 90% of the Indians fail to receive adequate sleep, with up to 58% believing that their work efficiency is affected by poor sleep quality and 11% falling asleep during work. However, only 2% of those with sleep-deprivation discuss their insomnia with a physician [2]. Mental disorders are a strong social stigma in India; insomnia often goes underreported like other mental disorders (such as anxiety and depression) because consulting a psychiatrist is often considered a taboo [3, 4]. A global survey entitled “Better Sleep, Better Health: A global look at why we’re still falling short on sleep” – conducted across 13 countries including the USA and UK – reported a very high prevalence of poor sleep in India [1]. In South India, the urban population seems to be more predisposed to difficulty in initiating and maintaining sleep than their rural counterparts [5]. Lack of awareness, coupled with inadequate health seeking behaviour, possibly underemphasizes the importance of healthy sleep [5]. The prevalence of insomnia is also high in North India – with over 75% patients reporting poor sleep quality upon hospital admission [6].

Sleep-wake cycle is greatly disrupted with ageing. Sleep apnoea and insomnia appear to be the major sleep problems among the elderly; approximately 50% of the elderly report difficulty initiating as well as maintaining sleep [7]. Alteration of sleep architecture includes longer peripheral stages of sleep (N1 and N2) and shorter stages of deep sleep (N3) or REM sleep. Insomnia in geriatric population is frequent, yet unresolved [8]. Although many diseases often contribute to insomnia, one cannot generalize that all comorbidities have a deleterious effect on sleep [9]. On the contrary, inadequate sleep is associated with higher risk as well as poorer prognosis of chronic diseases such as diabetes and cardiovascular diseases [10, 11]. Moreover, poor subjective sleep quality and inadequate sleep duration adversely affect the overall health-related quality of life [12]. In particular, sleep quality and duration are often compromised among the hospitalized patients due to pain, acute illness, anxiety, medical intervention, environmental noise and lights [13, 14].

Sedative-hypnotic drugs (primarily benzodiazepines (BZDs) and non-BZDs) are the mainstay for insomnia. To ensure the rational use of sedative-hypnotics, regulatory bodies (such as UK’s National Institute for Health and Care Excellence) have recommended further studies to evaluate the impact of hypnotics on the improvement of sleep quality and daytime sedation. Pittsburgh Sleep Quality Index (PSQI), a standardized questionnaire by the University of Pittsburgh, is a reliable tool to evaluate sleep quality [15]. Employing this questionnaire, we evaluated the sleep quality of inpatients undergoing short-term oral sedative-hypnotic therapy in a tertiary care hospital setting in South India.

This observational, pre-post study was designed to assess the sleep quality among in-patients undergoing oral sedative-hypnotic therapy. We obtained a modified one-week version of Pittsburgh Sleep Quality Index Past Week (PSQI_PW) from the University of Pittsburgh. We conducted in-depth patient interviews on the day of hospital admission (pre-score) and on the day of discharge or 7 days after hospital admission (post-score), whichever happened earlier. We also report on the factors influencing sleep quality, the sedative-hypnotic prescribing pattern, and patient-reported adverse effects of sedative-hypnotic drugs. We use the terms 'therapy' and 'treatment' interchangeably in this manuscript.

We found that inpatients who complained of trouble initiating or maintaining sleep had poor or very poor sleep quality scores. Our findings are in accordance with previous reports of the untreated burden of insomnia among inpatients, especially the elderly [8, 9, 19]. A previous study in Brazil reported that abrupt awakenings among inpatients were primarily caused by comorbid conditions, uncomfortable bedding, nursing routine, fear, pain, breathlessness and room temperature. Patients also attributed insomnia to the comorbid condition such as fracture-induced pain, lung disease induced cough, or dyspnoea [19]. Poor sleep not only affects overall health, but also has negative impact on one’s appearance, mood, motivation and concentration [1].

In our study, short-term oral sedative-hypnotic therapy improved sleep quality among majority of the inpatients who experienced insomnia. Comorbidity-induced insomnia benefited from sedative-hypnotic therapy; maximally in patients with hospitalizations due to fractures. The small proportion (7%) of the study population who reported persistent insomnia after sedative-hypnotic discontinuation also reported very poor prognoses; neither did their existing health condition or underlying diseases improve upon hospitalization, nor did they benefit much from sedative-hypnotic therapy.

Literature indicates that sleep quality is a proxy prognostic marker for comorbid conditions [20‐23]. Therefore, timely diagnosis and management of insomnia – with lifestyle/behavioural modifications and/or sedative-hypnotics therapy as appropriate – is important. With respect to sedative-hypnotic therapy, the choice of drug, dose frequency and duration of therapy must be customized to each patient’s characteristics and condition of severity [24]. However, in India, there is lack of clinical guidelines for prescribing of sedative-hypnotics among patients with varying diagnoses and circumstances. Our qualitative interviews indicate that utilization of short-term sedative-hypnotic therapy in patients with comorbidity-induced insomnia is largely driven by physician’s judgement.

The treatment of insomnia remains somewhat unchanged for decades, ever since the introduction of BZDs in the 1960s and Z-drugs in the 1990s. From 2006 through 2011, zolpidem prescriptions underwent a steady rise in the US [25]. Europe has witnessed a decline in BZD prescriptions with a corresponding rise in Z-drug prescriptions. This trend continues in spite of contrary guidelines issued by the UK’s National Institute for Health and Care Excellence (NICE), which favour the least expensive hypnotic i.e. BZDs [26‐28]. The European Guidelines for Diagnosis and Treatment of Insomnia (2017) recommends BZD and Z-drugs as first line pharmacotherapy choice, but does not mention the differential impact of these two drugs on sleep quality [29].

Although zolpidem went on to become the most prescribed sedative-hypnotic in the US and UK over the last decade, little has this transition affected the practice in India [30, 31]. Our findings are concordant with most of the recent drug utilization evaluation studies in India, in which BZDs continue to be preferred largely over Z-drugs [31, 32]. Only 26% of the patients were prescribed zolpidem, the only Z-drug prescribed.

Although some literature hints the superiority of zolpidem over BZDs in terms of physician preference, the overall comparative evidence regarding sleep quality is inconclusive [33, 34]. In our analyses comparing zolpidem and BZDs, while zolpidem led to greater improvement in overall sleep quality among the patient, the differences in improvement were not statistically significant upon adjusting for age, gender and primary diagnosis for hospitalization. Our qualitative interviews suggest that majority of the physicians support zolpidem; however, introducing a change in the existing practice is likely to be slow because junior doctors tend to follow their seniors, who have been habituated to prescribing BZDs for decades. The tendency to follow key opinion leaders is likely to be driven by the ‘prestige-based hierarchy’ – prevailing in India [35]. Thus, individual clinical judgements of key opinion leaders appear to override clinical efficacy when the practice is primarily physician-dominated.

The inclination towards BZDs persists in India possibly due to the paucity of literature supporting the superiority of Z-drugs over BZDs. As mentioned earlier, India neither possesses nor follows standardized treatment guidelines that govern the use of sedatives. The poorly understood concept of safety and adverse effect profile of Z-drugs vs. BZDs presents a problem especially among geriatric patients and other high risk groups [36]. Nevertheless, with physicians in both the US and UK preferring zolpidem over the years, the prevailing popularity of BZDs in India is unanticipated, given the fact that Indian pharmaceutical regulations are preferentially biased towards ‘imported’ rules of practice.

On another note, poor marketing practices might have also contributed to zolpidem’s low utilization in India. A controversial advertisement campaign by Abbott Pharmaceuticals in 2011 – aiming to promote its brand of zolpidem in India – evoked widespread criticism by doctors. While the pharma-giant probably overexploited the findings of a study that associated poor sleep with increased mortality due to cardiovascular disease, the doctors pointed out that the practice of ‘pill popping’ is more harmful [37].

Cost concerns do play a vital role in the choice of drugs, especially in the rural and low socioeconomic status areas in India. BZDs – being relatively cheaper – are thus preferred over zolpidem and other Z-drugs. Despite the fact that this pattern in India complies with the NICE recommendations of prescribing hypnotic of minimal cost, sleep quality is not a factor to be neglected. With India passing The Mental Healthcare Act of 2017, ailments mentioned in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) become eligible for coverage under India’s health insurance policies [38]. As our qualitative results suggest, the choice of the sedative-hypnotic must also take into account the patients’ underlying diseases. This creates the compelling need for appropriate evidence-based treatment guidelines for sleep disorders among inpatients. We recommend more studies (such as prospective trials and/or real-world studies) evaluating the comparative efficacy and safety of zolpidem vs. benzodiazepines among patient groups with varying demographic and clinical characteristics, in order to inform treatment guidelines and clinical practice.

Our study, however, has few limitations. Our analyses did not adjust for some potential confounders – such as patient’s health status, severity of underlying condition and other comorbidities – that may influence the outcomes of sedative-hypnotic drugs in management of insomnia. Furthermore, our findings from a single tertiary healthcare centre in Kerala state cannot be extrapolated to other Indian states with different health indicators, disease burden, patient demographics and socio-economic status.

In conclusion, with sleep quality being an important prognostic marker during hospitalization, lack of standard guidelines for utilization as well as continuous monitoring of the efficacy of sedative-hypnotics needs to be addressed. Our study suggests the possible superiority of zolpidem over BZDs in improving sleep quality in hospitalized patients, however these results are not conclusive. We underline the need of more clinical studies comparing the impact of zolpidem and BZDs on sleep quality in order to inform clinical guidelines and promote evidence-based use of sedative-hypnotics.