Aims: To test the safety of new buprenorphine oral lyophilisate wafer (“bup-lyo”) versus standard sub-lingual buprenorphine (“bup-SL”). Design: Randomised (2:1) open-label study; opioid-dependent subjects; subsequent partial cross-over. Settings: Specialised clinical trials facility and addictions treatment facility. Participants: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients co-using alcohol, cocaine and benzodiazepines (below thresholds). Measurements: Respiratory function (respiratory rate, pulse-oximetry); medication hold and dose adequacy; opiate withdrawal signs and symptoms; tablet disintegration times; treatment retention. Pharmacokinetics (PK) for plasma buprenorphine and norbuprenorphine (n = 11). Findings: Oral lyophilised buprenorphine (“bup-lyo”) completely dissolved within 2 min for 58 vs. 5% for “bup-SL.” Dose titration resulted in similar maintenance dosing (10.8 vs. 9.6 mg). There were no significant between-group differences in opiate-withdrawal phenomena, craving, adequacy of “hold,” respiratory function. No serious adverse events (AEs), nor “severe” AEs, although more AEs and Treatment-Emergent AEs with “bup-lyo” (mostly “mild”). PK found greater bioavailability of buprenorphine with “bup-lyo” (but not norbuprenorphine). Conclusions: Orally disintegrating buprenorphine oral lyophilisate wafer disintegrated rapidly. No increased respiratory depression was found and clinically no difference between medications was observed. PK found substantially increased bioavailability of buprenorphine (but not of nor-buprenorphine) with “bup-lyo” relative to “bup-SL.” In supervised dosing contexts, rapidly disintegrating formulations may enable wider buprenorphine prescribing.
Exploratory investigation found respiratory depression more strongly associated with norbuprenorphine than with buprenorphine. This accords with animal studies. .
Introduction
Intravenous (iv) paracetamol can cause severe hepatotoxicity and lead to death if inappropriately prescribed1. It is increasingly being used for post-operative pain and pyrexia2. There is a lack of awareness that paracetamol should be prescribed by weight when used in certain higher risk groups1,2; including those weighing less than 50kilos and in malnourished patients3. This study assessed iv paracetamol prescribing in patients at increased risk of hepatotoxicity.
Methods
Drug charts and medical records from 5 wards (3 surgical and 2 medical including 1 gastroenterology ward) were assessed prospectively over 3 days. All patients prescribed paracetamol were identified; those receiving iv preparations were included. The age, sex and weight were recorded in conjunction with the dose, route and number of paracetamol doses received by each patient. Intravenous doses were identified by countersignatures on drug charts or where iv was the only route indicated. Medical records were reviewed for a history of alcohol excess, chronic liver disease, chronic kidney disease (CKD), eating disorders, and those taking CYP450 inducing medications.
Results
59 patients were receiving paracetamol via any route. The average age was 74.6 years old (range 32–86). 25 patients had received iv paracetamol with 12/25 (48%) receiving the drug only via the iv route. The mean number of consecutive doses was 4.44 (range 1–28). 3 patients had CKD, 3 patients were on the CYP450 inducer Rifampicin and 1 patient had an eating disorder and CKD. 2 patients receiving iv doses were under 50 kg, one of which had CKD. Of the 9 patients deemed to be at risk of iatrogenic paracetamol induced hepatotoxicity, 0% had paracetamol prescribed at the recommended reduced dose of 3g per day.
Conclusion
This study demonstrates that intravenous paracetamol was not being prescribed appropriately. Intravenous paracetamol should be reduced in high risk groups to 3g per day (15mg/kg/24 hours). With 25–37% of all hospital inpatients being deemed at risk of malnourishment4 a large patient cohort is at risk of paracetamol induced liver injury. Assessment of nutritional status and improved awareness of higher risk patients is needed to avoid iatrogenic paracetamol induced hepatotoxicity through poor prescribing.
Disclosure of Interest
None Declared
References
Fatal Accident Inquiry into the death of Danielle Welsh. Available at: [Accessed15 Nov 2012]
Gray T, Hoffman R, Bateman D. Intravenous paracetamol – an international perspective of toxicity. Clinical Toxicology 2011; 49 : 150–152.
British National Formulary. Sept 2012.64 : 264–265
BAPEN 2012 -, [Accessed 3rd Jan 2013].
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