Advances and limitations in the evaluation of analgesic combination therapy.

Combination therapy using multiple drugs or modalities that target multiple mechanisms is common practice in the treatment of chronic pain. The benefit of combination therapy is purported to lie in its ability to provide improved efficacy with reduced toxicity. However, there are few published trials evaluating combination analgesics. Therefore, clinical choices regarding treatments, doses, and schedules tend to be determined empirically from innumerable drug combinations and permutations. Synergism is in part dependent on the pain condition, drug-drug interactions, and dose responses of the individual treatment components (among known and unknown factors), and a quantification of synergistic interactions would enable a rational approach to the use of combination analgesic therapy. Traditionally, drug interactions were evaluated by first establishing dose-response relationships of the individual component drugs and the combination in fixed dose ratios, followed by constructing isobolograms that would then allow a detailed statistical analysis. This strategy is at best challenging to perform in chronic analgesic trials. This article discusses the gold standard analytic approach to evaluating combination therapies (isobolograms), various permutations of this approach in human subjects, and the challenges of designing randomized controlled clinical trials that assess synergism between two therapies.

Self-Inclusion Complexes Derived from Cyclodextrins: Synthesis and Characterization of 6(A),6(B)-Bis-O-[p-(allyloxy)phenyl]-Substituted beta-Cyclodextrins.

The syntheses, structures, and spectroscopic properties of 6(A),6(B)-bis-O-[p-(allyloxy)phenyl]-substituted beta-cyclodextrins have been investigated. Selective activation of the 6(A),6(B)-hydroxy groups was carried out by treating heptakis(2,3-di-O-methyl)-beta-cyclodextrin (1) with 2,4-dimethoxybenzene-1,5-disulfonyl chloride to give 6(A),6(B)-bissulfonate ester 2 in a yield of only 3%. This material was treated with sodium p-(allyloxy)phenoxide in DMF to form 6(A),6(B)-bis-O-[p-(allyloxy)phenyl]-heptakis(2,3-di-O-methyl)-beta-cyclodextrin (3), which had two isomers. One (3A) has the two p-(allyloxy)phenyl arms directed away from the cyclodextrin cavity, and the other (3B) has one of the p-(allyloxy)phenyl groups through the cavity to form a self-inclusion complex. When either 3A or 3B was treated with methyl iodide and sodium hydride, the resulting permethylated 6(A),6(B)-bis-O-[p-(allyloxy)phenyl]heptakis(2,3-di-O-methyl)-6(C),6(D),6(E),6(F),6(G)-penta-O-methyl-beta-cyclodextrin (4) was composed of two isomers, in which 4B is a self-inclusion complex. 3A and 3B also can be converted into a mixture of 3A and 3B in strong base but not when melted in the absence of base. 4A and 4B do not isomerize. Detailed 1D and 2D NMR spectroscopic studies were carried out to characterize the structures of these new compounds, and molecular mechanics techniques were used to explain the experimental facts.