Use of and barriers to access to opioid analgesics: a worldwide, regional, and national study.

BACKGROUND: Despite opioid analgesics being essential for pain relief, use has been inadequate in many countries. We aim to provide up-to-date worldwide, regional, and national data for changes in opioid analgesic use, and to analyse the relation of impediments to use of these medicines. METHODS: We calculated defined daily doses for statistical purposes (S-DDD) per million inhabitants per day of opioid analgesics worldwide and for regions and countries from 2001 to 2013, and we used generalised estimating equation analysis to assess longitudinal change in use. We compared use data against the prevalence of some health disorders needing opioid use. We surveyed 214 countries or territories about impediments to availability of these medicines, and used regression analyses to establish the strength of associations between impediments and use. FINDINGS: The S-DDD of opioid analgesic use more than doubled worldwide between 2001-03 and 2011-13, from 1417 S-DDD (95% CI -732 to 3565; totalling about 3.01 billion defined daily doses per annum) to 3027 S-DDD (-1162 to 7215; totalling about 7.35 billion defined daily doses per annum). Substantial increases occurred in North America (16,046 S-DDD [95% CI 4032-28,061] to 31,453 S-DDD [8121-54,785]), western and central Europe (3079 S-DDD [1274-4883] to 9320 S-DDD [3969-14,672]), and Oceania (2275 S-DDD [763-3787] to 9136 S-DDD [2508-15,765]). Countries in other regions have shown no substantial increase in use. Impediments to use included an absence of training and awareness in medical professionals, fear of dependence, restricted financial resources, issues in sourcing, cultural attitudes, fear of diversion, international trade controls, and onerous regulation. Higher number of impediments reported was significantly associated with lower use (unadjusted incidence rate ratio 0.39 [95% CI 0.29-0.52]; p<0.0001), but not when adjusted for gross domestic product and human development index (0.91 [0.73-1.14]; p=0.4271). INTERPRETATION: Use of opioid analgesics has increased, but remains low in Africa, Asia, Central America, the Caribbean, South America, and eastern and southeastern Europe. Identified impediments to use urgently need to be addressed by governments and international agencies. FUNDING: International Narcotics Control Board, UN.

Formulation development of morphine sulfate sustained-release tablets and its bioequivalence study in healthy Thai volunteers.

The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand. The physicochemical properties of the formulated and commercial tablets were determined and compared. The bioequivalence investigation was carried out in 15 healthy male volunteers who received a single dose in a randomized two-way crossover design. After dosing, serial blood samples were collected for a period of 24 h. Morphine concentration was assayed by high-performance liquid chromatography with electrochemical detector. The log-transformed C(max) and AUC(s) were statistically compared by analysis of variance, and the 90% confidence intervals (CIs) of the ratio of the log-transformed C(max) and AUC(s) between the most promising developed formulation and the commercial product were determined. It was found that the dissolution rate profile of a developed formulation was similar to the commercial brand. Their similarity and difference factors were well within limits. In the bioequivalence study, the AUC(last) and AUC(inf) between the test and the reference products were not statistically different (p = 0.227 and p = 0.468, respectively), with the 90% CIs of 83.4-102.6% and 87.7-139.4%, respectively. However, the C(max) of the two formulations was significantly different (p = 0.019). The 90% CI of the developed formulation was 72.0-93.0% compared to the commercial product. In vitro dissolution of locally prepared morphine sulfate sustained-release tablets was comparable to commercial brand. However, the results justified the conclusion of lack of bioequivalence of the developed product to the commercial one.

Formulation development and stability testing of oral morphine solution utilizing preformulation approach.

PURPOSE: Prefomulation approach utilizing the fractional-ordered randomized blocked design was employed for the formulation development and stability testing of morphine solution. METHODS: Factors expecting to affect the stability of morphine were evaluated, i.e., vehicle, antioxidant, chelating agent, and pH of the solution. Eight formulations of a possible 16 were prepared according to the block design. The stability of the preparations was tested after 35 days of storage. The data of preformulation study were used for formulation development. RESULTS: The presence of glycerin and ethylenediamine-tetraacetic acid in the formulation, and the pH of the solution adjusted to 4, stabilized morphine. The concentration of morphine decreased drastically in the formulations containing sodium metabisulfite, and those pH adjusted to 6. After 35 days, only 65% of morphine was found in the formulation containing sodium metabisulfite and pH adjusted to 6. The results of preformulation study were used for preparing oral morphine preparations. Samples were kept in amber glass bottles and stored at 4 degrees C and 25 degrees C/75% RH for 13 months. No precipitation of the four formulations was detected. Only a decrease of odor and a small increase of pH value of the preparations (< 0.3 units) were observed. More than 97% of morphine remained in all samples. The samples were free from microbial contamination. CONCLUSION: Stable morphine solution formulations can be achieved with the utilization of the preformulation approach. They were stable more than 13 months when stored at 4 degrees C and 25 degrees C/75% RH.