Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans

Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans. a region with negligible ORs, the occipital cortex, to control for tracer binding. OR availability in each ROI was expressed as a [11C]-carfentanil distribution volume ratio (DVR), with higher values indicating greater OR availability. Images were adjusted for cerebral blood flow (which can alter tracer uptake) and radioactive scatter (which can alter precision), then co-registered with an anatomical MRI brain scan. In these studies, ROIs included inferior prefrontal cortex (Brodmann area 10 [BA 10]), subgenual and rostral divisions of the anterior cingulate cortex (BA 25 and BA 32), caudate nucleus, thalamus, nucleus accumbens, and amygdala. In each study the reader should note time(s) at which scanning occurred relative to the daily BUP dose. BUP plasma concentrations peak about 1 hr after SL administration and decrease throughout the day until the next dose. Similarly, OR availability should decrease shortly after the BUP dose and increase until the next dose. Thus, measures taken 4 hr after the daily dose (the earliest post-dose time that has been studied), likely reflect sub-maximal PTZ-343 reductions in OR availability. It is not feasible to conduct within-day PET time-course studies, therefore, knowledge of peak BUP concentrations must be extrapolated from concentration data, which can be sampled more frequently. 2.1.2. Mathematical (simulated) estimation of in vivo OR availability To estimate proportional receptor binding, one can also use a pharmacological analytical model (Black and Leff, 1983; Zernig et al., 1996) to derive a measure of medication intrinsic efficacy, relative to placebo control, that corresponds to the fraction of receptors (putatively, ORs) bound by BUP when half-maximum [ED50] heroin responses are produced. Comer et al. (2005) estimated efficacy of BUP blockade using an equation that accounts for: (1) receptor pool size under control conditions, (2) maximum attainable response, (3) opioid agonist concentration, (4) dissociation constant, and (5) transducer function that maps receptor binding to observed response. Using these inputs, PTZ-343 computer software finds a best-fit curve to the observed data, and derives Rabbit Polyclonal to BCL7A parameters from these curve fits. 2.2. Methodological challenges to studying and interpreting OR availability We first review methodological issues related to the receptor studies reviewed herein, as these influence interpretation and application of experimental findings to clinical practice settings. We advise clinicians and policymakers to be cautious in their conclusions due PTZ-343 to these important caveats. 2.2.1. Definition of opioid blockade There is no gold-standard operational definition for clinically meaningful opioid blockade, i.e., the degree to which medications such as BUP (or methadone or naltrexone) attenuate exogenous opioid effects. Blockade is important in reducing opioid agonistinduced effects such as subjective ratings related to abuse (e.g., liking), reinforcing effects (self-administration) or medical problems (e.g., respiratory depression). Yet, we do not know the threshold of brain OR availability required for specific clinical effects (withdrawal suppression, blockade), nor for which types of patients, abused opioids, or routes of administration. Lack of such criteria is relevant for scientists, clinicians, and policymakers (e.g., FDA, state agencies, and insurance providers). This issue has precedents in the context of methadone treatment, as there have been historical divisions amongst clinicians and policymakers regarding whether higher-dose or lower-dose methadone is preferable. The clinical trials literature offers consistent support for the policy that, when safe for the individual patient, higher maintenance doses that provide blockade in addition to withdrawal suppression generally produce better outcomes than lower doses (Siassi et al., 1977; Ling et al., 1996, 1998; Strain et al., 1993, 1999). BUP binding to human brain ORs displaces endogenous and exogenous opioids, and thereby reduces OR availability that, in turn, prevents withdrawal and attenuates effects of exogenous opioids. Although these features do not directly determine clinical practice, the association between greater pre-treatment opioid use and higher prescribed BUP doses suggests OR binding may implicitly guide practice. A stronger version of this argument is that PTZ-343 there is a volunteers for their PTZ-343 drug use, who typically do not remain drug-free during outpatient periods without abstinence-contingent incentives (Greenwald, 2008). Participants underwent experimental brain imaging and other procedures under to minimize confounds. Thus, generalizability of findings to individuals dependent on.