Chapter 2: Prescribing and administration of drugs and the deaths that resulted

Families’ concerns have focused predominantly on the use of opioids, rightly so in the light of their potency and potential for harm. The Panel’s analysis of clinical records from the hospital shows that opioids were frequently given to patients in conjunction with other drugs that affect the central nervous system – mainly midazolam and hyoscine, but also sometimes haloperidol, thioridazine or other sedatives.

Midazolam is a short-acting anxiolytic or tranquilliser which was frequently given in conjunction with diamorphine to patients at the hospital. It is a member of the benzodiazepine group, the best-known example of which is diazepam (Valium). These drugs act on a different set of specific receptors in the nervous system, which are independent of the opioid receptor system. As with opioids, there is a specific antagonist to benzodiazepines – flumazenil – which is used to treat overdose and poisoning.

Midazolam is normally given by injection. Its main use is in anaesthetics and to achieve ‘conscious sedation’, particularly for painful or uncomfortable procedures such as endoscopy or dressing burns. It is often used in combination with a short-acting opioid such as fentanyl to produce profound sedation and analgesia while the patient remains conscious and able to cooperate with the clinician. It has anticonvulsant actions and is used in some forms of epilepsy. It has a place in palliative care (when it is given by continuous subcutaneous infusion) for two specific purposes: to treat seizures, or in patients who are very restless or agitated (sometimes referred to as ‘terminal agitation’). Midazolam has no analgesic effects.

Temazepam is another benzodiazepine, which was sometimes given by mouth as a night sedative to patients at the hospital. Clomethiazole is a non-benzodiazepine, non-opioid sedative for severe insomnia, and also for agitation and restlessness in the elderly, which was also occasionally given.

Hyoscine is an anticholinergic (atropine-like) drug used for excessive respiratory secretions or bowel colic. It is also sedating and can produce amnesia; the drowsiness and dry mouth caused by old-fashioned travel sickness remedies (many of which contain hyoscine) are due to their anticholinergic effects. Hyoscine was frequently given to patients at the hospital, usually in combination with diamorphine and midazolam. In some patients, especially the elderly, hyoscine can cause a ‘central anticholinergic syndrome’ with excitement, ataxia (loss of muscle coordination), hallucinations and behavioural disturbances.

Haloperidol is an antipsychotic drug used mainly in the treatment of schizophrenia and other psychoses. Its use in low doses is also well established for agitation and restlessness in the elderly. It has no analgesic effects and is only mildly sedating. Chlorpromazine, an antipsychotic drug of the phenothiazine group, which is also a powerful sedative, was also sometimes given for agitation and restlessness.

Thioridazine is another antipsychotic drug of the phenothiazine group. It was used mainly in schizophrenia but also to treat agitation and some of the symptoms of dementia. It was withdrawn from the market in all European Union member states in 2005 because of an unacceptably high risk of serious cardiac side effects.

Medication used in the hospital reflected the wide range of conditions of the patients admitted and included diuretics (for heart failure), antihypertensives, digoxin, antidepressants and anxiolytics, anti-inflammatory drugs for arthritis, and antibiotics.

A drug interaction occurs when the effect of one drug is modified by the prior or concurrent administration of another. The prescribing of opioids and other drugs in combination is known to expose patients to the risk of drug interactions. The pharmacology of drug interactions is complex. But the potential for increased sedation and respiratory depression when opioids and benzodiazepines are used together has been recognised and publicised since at least the 1980s. The impact may be additive: the combined effect is the sum or the part sum of the drugs individually. Or it may be supra-additive or synergistic: the combined impact is greater than the sum of the individual effects.

In general, the effect of these drugs when given together is at least additive, and may be synergistic.¹⁴ The risk of using them in combination has been consistently documented in the BNF. In particular, it has long been known that when given together, opioids and midazolam cause enhanced sedation, respiratory depression and lowered blood pressure. Moreover, the effects of age and/or renal failure discussed above further increase the risk, as does co-administration of other sedatives such as hyoscine, chlorpromazine or thioridazine.

Phenothiazine antipsychotics such as chlorpromazine and thioridazine have been consistently shown to produce exaggerated falls in blood pressure and depressed respiration when given in combination with opioid analgesics. A comprehensive review of opioid interactions in 1993 concluded:¹⁵