Dihydrocodeine: safety concerns

Anaesthesia, 1958

Anaesthesia, 1990

A randomised, double-blind study of 90 patients after cardiac bypass surgery was undertaken to assess the relative analgesic efficacies of normal-and controlled-release oral dihydrocodeine. Patients received either placebo, normal-release dihydrocodeine. or controlled-release dihydrocodeine at regular intervals on the first to third days after operation. This w'as supplemented in all groups by intravenous morphine administered on demand by a patient-controlled analgesia system. Morphine requirements in the control group were signijicantly greater during this 48-hour period than in either ofthe active groups (p < 0.01), but there was no statistically significant difference between the two active preparations.

Anaesthesia, 1991

British Journal of Clinical Pharmacology, 2001

Aims It is not clear whether the analgesic effect following dihydrocodeine (DHC) administration is due to either DHC itself or its metabolite, dihydromorphine (DHM). We examined the relative contribution of DHC and DHM to analgesia following DHC administration in a group of healthy volunteers using a PK-PD link modelling approach. Methods A single oral dose of DHC (90 mg) was administered to 10 healthy volunteers in a randomised, double-blind, placebo-controlled study. A computerized cold pressor test (CPT) was used to measure analgesia. On each study day, the volunteers performed the CPT before study medication and at 1.25, 2.75, 4.25 and 5.75 h postdose. Blood samples were taken at 0.25 h (predose) and then at half hourly intervals for 5.75 h postdose. PK-PD link modelling was used to describe the relationships between DHC, DHM and analgesic effect. Results Mean pain AUCs following DHC administration were signi®cantly different to those following placebo administration (P=0.001). Mean pain AUC changes were 91 score. s x1 for DHC and x17 score. s x1 for placebo (95% CI=t36.5 for both treatments). The assumption of a simple linear relationship between DHC concentration and effect provided a signi®cantly better ®t than the model containing DHM as the active moiety (AIC=4.431 vs 4.668, respectively). The more complex models did not improve the likelihood of model ®ts signi®cantly. Conclusions The ®ndings suggest that the analgesic effect following DHC ingestion is mainly attributed to the parent drug rather than its DHM metabolite. It can thus be inferred that polymorphic differences in DHC metabolism to DHM have little or no effect on the analgesic affect.

British Journal of Clinical Pharmacology, 2001

The pharmacokinetics of dihydrocodeine (DHC) and its active metabolite dihydromorphine (DHM) were assessed after a single oral dose of DHC and after increasing doses of DHC at steady-state. Methods Twelve healthy male volunteers (18-45 years, CYP2D6 extensive metabolizers (EMs), MR<1 took a single oral dose (s.d.) of DHC 60 mg after breakfast. After 60 h DHC 60 mg was administered twice daily for 3 days, the dose was increased to 90 mg twice daily for 3 days, the final dose of 120 mg was administered twice daily for 3 days (multiple dose: m.d.). Blood sampling and urine collection: during 60 h after s.d. and during 12 h after m.d. Results No significant differences in the area under the curve (AUC) of both, DHC and DHM could be detected after a single oral dose of 60 mg DHC (AUC (0,2)) and during steady-state doses of 60 mg DHC (AUC(0,12 h)). During increasing steady-state doses of DHC, the data showed a dose linearity of AUC, maximal serum concentration (C max ) and minimal steady-state serum levels (C ss min) of both, DHC and DHM ( P<0.0001), point estimates of DHC dose corrected AUCs were well within the bioequivalence range (60 mg: 0.989; 90%CI 0.951-1.028, 90 mg: 0.997; 90%CI 0.959-1.036, 120 mg: 0.977; 90%CI 0.940-1.016). O-demethylation from DHC to DHM remained constant within the increasing steady-state doses of DHC in the 12 extensive metabolizers of CYP2D6. Conclusions In the studied dose range (60-120 mg ) the pharmacokinetics of DHC and its active metabolite DHM are linear in EMs of CYP2D6.

Brit J Clin Pharmacol, 2001

The pharmacokinetics of dihydrocodeine (DHC) and its active metabolite dihydromorphine (DHM) were assessed after a single oral dose of DHC and after increasing doses of DHC at steady-state. Methods Twelve healthy male volunteers (18-45 years, CYP2D6 extensive metabolizers (EMs), MR<1 took a single oral dose (s.d.) of DHC 60 mg after breakfast. After 60 h DHC 60 mg was administered twice daily for 3 days, the dose was increased to 90 mg twice daily for 3 days, the final dose of 120 mg was administered twice daily for 3 days (multiple dose: m.d.). Blood sampling and urine collection: during 60 h after s.d. and during 12 h after m.d. Results No significant differences in the area under the curve (AUC) of both, DHC and DHM could be detected after a single oral dose of 60 mg DHC (AUC (0,2)) and during steady-state doses of 60 mg DHC (AUC(0,12 h)). During increasing steady-state doses of DHC, the data showed a dose linearity of AUC, maximal serum concentration (C max ) and minimal steady-state serum levels (C ss min) of both, DHC and DHM ( P<0.0001), point estimates of DHC dose corrected AUCs were well within the bioequivalence range (60 mg: 0.989; 90%CI 0.951-1.028, 90 mg: 0.997; 90%CI 0.959-1.036, 120 mg: 0.977; 90%CI 0.940-1.016). O-demethylation from DHC to DHM remained constant within the increasing steady-state doses of DHC in the 12 extensive metabolizers of CYP2D6. Conclusions In the studied dose range (60-120 mg ) the pharmacokinetics of DHC and its active metabolite DHM are linear in EMs of CYP2D6.

Pharmacology and Toxicology, 2002

Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine-6-O-, dihydromorphine-3-O-and dihydromorphine-6-O-glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to m-, d-and k-opioid receptors. Codeine, morphine, d,l-methadone and levomethadone were used as controls. Displacement binding experiments were carried out at the respective opioid receptor types using preparations of guinea pig cerebral cortex and the specific opioid agonists [ 3 H]DAMGO (m-opioid receptor), [ 3 H]DPDPE (d-opioid receptor) and [ 3 H]U69,593 (k-opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0 nmol/l, respectively. All substances had their greatest affinity to the m-opioid receptor. The affinities of dihydromorphine and dihydromorphine-6-O-glucuronide were at least 70 times greater compared with dihydrocodeine (K i 0.3 mmol/ l), whereas the other metabolites yielded lower affinities. For the d-opioid receptor, the order of affinities was similar with the exception that dihydrocodeine-6-O-glucuronide revealed a doubled affinity in relation to dihydrocodeine (K i 5.9 mmol/ l). In contrast, for the k-opioid receptor, dihydrocodeine-6-O-and dihydromorphine-6-O-glucuronide had clearly lower affinities compared to the respective parent compounds. The affinity of nordihydrocodeine was almost identical to that of dihydrocodeine (K i 14 mmol/l), whereas dihydromorphine had a 60 times higher affinity. These results suggest that dihydromorphine and its 6-O-glucuronide may provide a relevant contribution to the pharmacological effects of dihydrocodeine. The O-demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic cytochrome P-450 enzyme CYP2D6, resulting in different metabolic profiles in extensive and poor metabolizers. About 7% of the caucasian population which are CYP2D6 poor metabolizers thus may experience therapeutic failure after standard doses.

PAIN®, 2014

Guidelines for opioid treatment of chronic non-malignant pain recommend long-acting over short-acting opioid formulations. The evidence for this recommendation is weak. This study is a randomized, doubleblind, double-dummy, 8-week comparison of long-acting dihydrocodeine tablets (DHC-Continus) with short-acting dihydrocodeine tablets in 60 patients with chronic non-malignant pain who were referred to a multidisciplinary pain clinic. All patients used codeine-paracetamol tablets before the trial, and paracetamol was added in both groups during the trial. The primary outcome was stability in pain intensity, measured as the difference between the highest and least pain intensity reported on an 11-point numerical rating scale in a 7-day diary. The secondary outcomes were differences in quality of life, quality of sleep, depression, and episodes of breakthrough pain between the 2 formulations. Spontaneously reported adverse events were recorded. In all, 38 patients completed the trial, and 22 withdrew before the end. The reasons for withdrawal were adverse events, lack of efficacy, or both, and were similar between the groups. There were no significant differences in stability of pain intensity between groups. There were no significant differences between groups in quality of sleep, depression, health-related quality of life, or adverse events. Breakthrough pain was experienced in both groups during the trial. Longacting dihydrocodeine was not observed to be superior for any of the outcomes in this trial. The results of this study do not support current guidelines recommending long-acting opioids.

Pharmacological Reports, 2012

Aim of the study was to assess dihydrocodeine (DHC) and metabolites concentrations and their correlations with DHC analgesia in cancer patients with pain. Thirty opioid-naive patients with nociceptive pain intensity assessed by VAS (visual analogue scale) > 40 received controlled-release DHC as the first (15 patients, 7 days) or as the second opioid (15 patients, 7 days). Blood samples were taken on day 2, 4 and 7 at each study period. DHC and its metabolites were assayed by HPLC. DHC provided satisfactory analgesia when administered as the first or the second opioid superior to that of tramadol. When DHC was the first opioid administered, DHC and dihydrocodeine-6-glucuronide (DHC-6-G) concentrations increased in the second and the third comparing to the first assay. A trend of nordihydromorphine (NDHM) level fall between the first and the third assay was noted; trends of dihydromorphine (DHM) level increase in the second relative to the first determination and decrease in the third compared to the second assay were observed. When DHC followed tramadol treatment a trend of DHC concentration increase in the second relative to the first assay was noted. DHC-6-G level increased in the second and in the third comparing to the first determination; NDHM and DHM concentrations were stable. DHC and DHC-6-G concentrations increased similarly during both treatment periods which suggest their prominent role in DHC analgesia. Few significant correlations were found between DHC dose, DHC and metabolites serum concentrations with analgesia suggesting the individual DHC dose titration.

Cochrane Database of Systematic Reviews, 2000

McQuay 1985 {published data only} McQuay HJ, Bullingham RES, Moore RA, et al. Zomepirac, dihydrocodeine and placebo compared in postoperative pain a er day-case surgery. The relationship between the e ects of single and multiple doses.