dihydromorphine and Pain

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.. 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.. Mean pain AUCs following DHC administration were significantly different to those following placebo administration (P = 0.001). Mean pain AUC changes were 91 score x s(-1) for DHC and -17 score x s(-1) for placebo (95% CI = +/- 36.5 for both treatments). The assumption of a simple linear relationship between DHC concentration and effect provided a significantly better fit 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 fits significantly.. The findings 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.

Topics: Administration, Oral; Adult; Analgesia; Analgesics, Opioid; Area Under Curve; Codeine; Cross-Over Studies; Dihydromorphine; Double-Blind Method; Female; Humans; Male; Models, Biological; Pain; Pain Measurement; Pain Threshold; Skin Physiological Phenomena

In a prospective study, including fifty consecutive patients with acute ureteral-stone pain, the patients were randomly distributed into two groups for treatment. There were given either an intravenous injection of indomethacin (Confortid) 50 mg, or a subcutaneous injection of 2 mg hydromorphine chloride-atropine (Dilaudid-atropin 1 ml). Patients in the latter group also received a suppository of prochlorperazine (Stemetil) 25 mg. The analgesic effect of the two drugs did not differ significantly. Indomethacin was quicker acting, probably due to the intravenous route of administration. The side effects were alike but those caused by indomethacin had a tendency to be milder and of shorter duration.

Topics: Adult; Analgesics; Atropine; Dihydromorphine; Humans; Indomethacin; Injections, Intravenous; Injections, Subcutaneous; Middle Aged; Morphine Derivatives; Pain; Prochlorperazine; Prospective Studies; Ureteral Calculi

The present study examined the pharmacology of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin (3,6-diacetyldihydromorphine). Like morphine, dihydromorphine and its acetylated derivatives all were highly selective mu-opioids in receptor binding assays. All the compounds were potent mu-selective analgesics, as shown by their sensitivity towards the mu-selective opioid receptor antagonists naloxonazine and beta-funaltrexamine. However, the actions of dihydromorphine and its analogs were readily distinguished from those of morphine, differences that were surprising in view of the very limited structural differences among them that consisted of only the reduction of the 7,8-double bond. Like heroin and morphine-6beta-glucuronide, the analgesic actions of dihydromorphine and its two acetylated derivatives were antagonized by 3-O-methylnaltrexone at a dose that was inactive against morphine analgesia. Antisense mapping also distinguished between morphine and the dihydromorphine compounds. Antisense oligodeoxynucleotides targeting exon 2 of the cloned MOR-1 gene decreased dihydromorphine analgesia and that of its acetylated derivatives, but not morphine analgesia. Conversely, the exon 1 antisense that effectively lowered morphine analgesia was inactive against dihydromorphine and its analogs. Finally, dihydromorphine and its analogs retained their analgesic activity in a mouse model of morphine tolerance, consistent with incomplete cross-tolerance. Together, these findings imply that the mu-opioid receptor mechanisms mediating the analgesic actions of dihydromorphine and its acetylated analogs are distinct from morphine and more similar to those of heroin and morphine-6beta-glucuronide.

Topics: Analgesics, Opioid; Animals; Dihydromorphine; Drug Tolerance; Heating; Heroin; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Morphine; Oligonucleotides, Antisense; Pain; Receptors, Opioid, mu; Reverse Transcriptase Polymerase Chain Reaction; Structure-Activity Relationship

Topics: Animals; Dihydromorphine; Enkephalins; Humans; Morphine; Pain; Receptors, Opioid; Receptors, Opioid, mu

We have developed a quantitative computerized subtraction technique to demonstrate in rat brain the regional distribution of mu1 sites, a common very-high-affinity binding site for both morphine and the enkephalins. Low concentrations of [D-Ala2, D-Leu5]enkephalin selectively inhibit the mu1 binding of [3H]dihydromorphine, leaving mu2 sites, while low morphine concentrations eliminate the mu1 binding of [3H][D-Ala2, D-Leu5]enkephalin, leaving delta sites. Thus, quantitative differences between images of sections incubated in the presence and absence of these low concentrations of unlabeled opioid represent mu1 binding sites. The regional distributions of mu1 sites labeled with [3H]dihydromorphine were quite similar to those determined by using [3H][D-Ala2, D-Leu5]enkephalin. High levels of mu1 binding were observed in the periaqueductal gray, medial thalamus, and median raphe, consistent with the previously described role of mu1 sites in analgesia. Other regions with high levels of mu1 binding include the nucleus accumbens, the clusters and subcallosal streak of the striatum, hypothalamus, medial habenula, and the medial septum/diagonal band region. The proportion of total specific binding corresponding to mu1 sites varied among the regions, ranging from 14% to 75% for [3H][D-Ala2, D-Leu5]enkephalin and 20% to 52% for [3H]dihydromorphine.

Topics: Animals; Autoradiography; Binding Sites; Brain Chemistry; Dihydromorphine; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Pain; Periaqueductal Gray; Raphe Nuclei; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Subtraction Technique; Thalamus

Topics: Animals; Brain; Calcium; Dihydromorphine; Male; Mice; Morphine; Naloxone; Pain; Potassium; Receptors, Opioid; Sodium; Stereoisomerism