Dose-related Effects of Controlled Release Dihydrocodeine on Oro-Cecal Transit and Pupillary Light Reflex

Abstract

It is well accepted that long-term administration of opioids results in a dose-related constipation. No data so far have demonstrated conclusively whether such constipation is also seen after intake of a controlled release formulation. It was therefore of interest to evaluate whether increasing doses of a controlled release formulation of dihydrocodeine (DHC, CAS 125-28-0) after oral administration also induces a dose-related increase in constipation. Additionally, it was of interest to study whether such a peripheral opioid-related side effect is also seen in another, central receptor-mediated effect, the constriction of the pupil, at clinically relevant doses. Twelve volunteers were given controlled release DHC (60 and 120 mg, respectively) or placebo orally within a randomized, double-blind cross-over study. In order to determine the degree of constipation, oro-cecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripherally and centrally mediated effects were compared to placebo. DHC at both dosages induced a significant (p < 0.01) prolongation of oro-cecal transit time when compared to placebo. However, prolongation of oro-cecal transit was not significantly longer when comparing the lower (60 mg) with the higher dose (120 mg). DHC also induced a significant (p < 0.005) depression of the pupillary light reflex from 53.9 mm (control) to 8.3 and 7.4 mm, respectively. Similar to intestinal transit, the pupillary light reflex was not significantly different among the two doses of DHC. Also, both dosages induced a similar amount of side effects. Tiredness and dry mouth were reported in 80% after both doses while vertigo was reported in 5% and 1% complained of headache. None of the volunteers reported nausea or emesis. It is concluded that opioid receptor sites, which are located in the plexus myentericus of the intestinal wall, are responsible for the delay in propulsion. Because of the controlled release of a fixed amount of DHC over time there is constant binding of the ligand followed by a constant conformational change of peripheral and central receptor sites. Thus constant release induces no dose-related increase in oro-cecal transit and inhibition of the pupillary light reflex.

Dihydrocodeine as an Opioid Analgesic for the Treatment of Moderate to Severe Chronic Pain

“…The main adverse effect of DHC is constipation which is probably not dose dependent and requires laxatives administration [26]. A possibility of more intense adverse effects and relative over dosage should be carefully considered in patients with renal impairment before commencing DHC therapy; in patients with renal failure other opioids such as buprenorphine [49], fentanyl [50] or methadone [51] should be preferred.…”

“…Freye et al explored the effects of two doses of DHC controlled-release tablets (60 and 120 mg) on constipation in 12 volunteers in a randomized, double-blind, cross-over, placebo-controlled study with one week wash-out [26]. The oro-cecal transit time was assessed by H2-exhalation test; lactulose 40 mg was administered 120 min after ingestion of DHC 60 mg, 120 mg and placebo.…”

Clinical Overview and Considerations for the Management of Opioid-induced Constipation in Patients With Chronic Noncancer Pain

“…In all cases, medical professionals should implement multimodal analgesic strategies to reduce the need for opioids, and patients should be titrated to the lowest effective opioid dose. Published results, however, do not indicate that there is a dose-response relationship between OIC and opioid dose, and many patients experiencing OIC continue to experience it even following dose titration to a lower opioid dose 83…”

Salivary dysfunction caused by medication usage

“…Similarly, a study evaluating controlled-release morphine sulfate reported several side effects including dry mouth [41]. Another opioid, dihydrocodeine, has been reported to cause dry mouth in 80% of the patients receiving it [42]. Tramadol, a synthetic, centrally acting analgesic agent, has also displayed dry mouth as one of its most common adverse reactions, with an incidence of 1.6-6.1% [43].…”