Modulation of peripheral endogenous opioid analgesia by central afferent blockade

BACKGROUND: Peripheral tissue injury causes a migration of opioid peptide-containing immune cells to the inflamed site. The subsequent release and action of these peptides on opioid receptors localized on peripheral sensory nerve terminals causes endogenous analgesia. The spinal application of opioid drugs blocks the transmission of nociceptive information from peripheral injury. This study investigates the influence of exogenous spinal opioid analgesia on peripheral endogenous opioid analgesia. METHODS: Six and forty-eight hours after initiation of continuous intrathecal morphine infusion and administration of Freund's complete adjuvant into the hind paw of rats, antinociceptive and antiinflammatory effects were measured by paw pressure threshold, paw volume, and paw temperature, respectively. Inflammation and quantity of opioid-containing cells were evaluated by immunocytochemistry and flow cytometry. Cold water swim stress-induced endogenous analgesia was examined 24 h after discontinuation of intrathecal morphine administration. RESULTS: Intrathecal morphine (10 micro g/h) resulted in a significant and stable increase of paw pressure threshold ( P< 0.05) without changing inflammation, as evaluated by paw volume, paw temperature, and flow cytometry ( P> 0.05). At 48 but not at 6 h after Freund's complete adjuvant, the number of beta-endorphin-containing cells and cold water swim-induced antinociception were significantly reduced in intrathecal morphine-treated rats compared with those treated with intrathecal vehicle ( P< 0.05). CONCLUSIONS: These findings suggest an interplay of central and peripheral mechanisms of pain control. An effective central inhibition of pain apparently signals a reduced need for recruitment of opioid-containing immune cells to injured sites.     

Surgical Approach to Invasive Adenocarcinoma of the Distal Esophagus (Barrett’s Cancer)

Barretts carcinoma, usually arising in the distal esophagus, must be considered a separate entity from squamous cell esophageal cancer. Epidemiology, etiology, patients risk profiles, biology of metastases, and prognosis differ markedly between these two major esophageal tumor types. The preoperative work-up of patients with Barretts cancer is primarily directed toward assessing the chances for R0 resection and estimating the risk of the patient to survive an esophagectomy. If R0 resection appears likely and the surgical risk is acceptable, the indication for an operative approach is given. From the oncologic point of view there is no difference between a radical transmediastinal approach and a transthoracic approach. A possible advantage of a transthoracic approach is the extension of lymphadenectomy to the upper mediastinum. Lymph node metastases in the upper mediastinum, however, usually indicate advanced lymphatic and subclinical systemic tumor dissemination, i.e., a poor prognosis even with extended surgery. Consequently the controversies about the surgical approach are reduced to technical and functional aspects. A better swallowing function argues for an intrathoracic anastomosis; the lower morbidity, for a cervical approach. We prefer transthoracic en bloc esophagectomy with an intrathoracic anastomosis in patients with moderate risk and early tumor stages. In all other patients radical transmediastinal esophagectomy with a cervical anastomosis is the procedure of choice. The overall 5-year survival rate of more than 40%, which is superior to most published data, supports this therapeutic strategy.     

Lower esophageal sphincter injection of a biocompatible polymer

Background: Endoscopic lower esophageal sphincter (LES) implantation of a biocompatible polymer is undergoing clinical trial as an alternative to pharmacologic and laparoscopic treatments for gastroesophageal reflux disease. The safety and efficacy of LES augmentation depend on accurate placement of the implant into the wall of the esophagus. To date, no study has demonstrated the prevalence and location of the intended implant. Methods: The study group consisted of nine patients with underlying esophageal disease severe enough to warrant esophagectomy. Three or four implants of 1 or 2 cc of Enteryx (a biocompatible ethylene–vinyl alcohol copolymer dissolved in dimethyl sulfoxide with micronized tantalum as a radiopaque marker) were placed at the squamocolumnar junction of each patient via a 4-mm, 23-gauge needle under endoscopic guidance. Fluoroscopy was utilized in all patients to facilitate endoscopic placement. Outcome measures included the prevalence and location of successful implantation into the wall of the esophagus. Results: Thirty of 34 implants (88%) were successfully placed into the wall of the esophagus. The remaining 4 were found lying subserosally or attached to the exterior of the gastroesophageal junction (GEJ). Fluoroscopically, the implants often tended to coalesce, forming arcs or a ring around the GEJ. Histologic examination revealed implantation into the deep submucosa contiguous with the circular muscle and within the muscularis propria in all patients, with implants occasionally extending into the subserosa. There were no untoward reactions identified. Conclusions: Endoscopically directed implantation of a biocompatible polymer into the esophageal wall can be accomplished with a high degree of accuracy. Injection via a 4-mm needle results in the placement of material along and within the muscular layers of the esophagus.     

Nicotine and drug interaction expectancies among methadone maintained cigarette smokers

Smoking rates among persons being treated with methadone for opiate dependence are exceptionally high. Nevertheless, there is debate about whether smoking cessation has a negative effect on substance abuse treatment outcomes. To understand patient perceptions of the interaction between smoking and illicit drug use, we administered the Nicotine and Other Substances Interaction Expectancies questionnaire (NOSIE) to 168 smokers—79% Caucasian and 48% female—at two methadone programs in Providence, Rhode Island. The four summed-rating scales of this 20-item instrument exhibited good to excellent internal-consistency reliabilities. The scales measured the effect of drug use on smoking (5 items, = .84), the effect of smoking on drug use (3 items, = .73), smoking to cope with drug urges (9 items, = .91), and the difficulty of concomitantly quitting smoking and drugs (3 items, = .72).

Most subjects believed drug use increased smoking, but that smoking did not trigger drug use. Relatively few reported smoking to cope with drug urges and most did not consider quitting smoking and quitting drug use to be incompatible goals. NOSIE was a reliable instrument that offers insight into patient expectations of the interaction of smoking and drug use.     

Treatment of sleep disturbance in alcohol recovery: a national survey of addiction medicine physicians

Sleep disturbance is common among patients in recovery from alcoholism and can precipitate relapse. Though sleep complaints are commonly managed with medication, little is known about their management among recovering alcoholic patients. We performed a postal survey of a self-weighted, random systematic sample of 503 members of the American Society of Addiction Medicine (ASAM) to examine addiction medicine physicians' medical management of sleep disturbance among patients in early recovery from alcoholism. After 3 mailings, 311 (62%) responded. Of responents, 64% have offered pharmacological treatment to an insomniac, alcoholic patient in the first 3 months after detoxification, but only 22% offered medication to more than half of such patients. Trazodone was the preferred therapy, chosen first by 38% of respondents, followed by other sedating antidepressants (12%), and antihistamines (12%). The mean duration of therapy for trazodone and other sedating antidepressants exceeded one month. Experts in addiction medicine appear reluctant to prescribe medication to sleep-disturbed patients in early recovery from alcoholism. When they do prescribe, trazodone, other sedating antidepressants and antihistamines are favored, despite limited evidence for or against this indication. Although the treatment of disordered sleep among alcoholic patients in early recovery may have merit to prevent relapse, controlled studies of these sleep agents are needed.     

A new model for drug discovery--meeting our societal obligation

The development of new models that will enable and encourage drug discovery in disease areas that are neglected by the industry is urgently needed. Here, one model is described that has been established to find treatments for neurodegenerative diseases.     

Paroxetine in the treatment of post-traumatic stress disorder: pooled analysis of placebo-controlled studies

Post-traumatic stress disorder (PTSD) is increasingly understood to be a medical disorder characterised by particular psychobiological dysfunctions that respond to specific treatments. Paroxetine is a selective serotonin re-uptake inhibitor that has been found effective in the treatment of major depression as well as a range of anxiety disorders. This paper reviews data on the use of paroxetine for the treatment of adult PTSD. There have been three 12-week, placebo-controlled studies of paroxetine in PTSD. As these followed a partly similar design, a pooled analysis of the studies is possible and is reported here. Paroxetine is effective in the short-term treatment of PTSD, resulting in significantly better response and remission rates than placebo, improving sleep disturbance and reducing each of the symptom clusters of PTSD, as well as the disability associated with this condition. The medication is effective in both male and female PTSD patients and whether or not there are comorbid disorders such as depression.     

Population health metrics: crucial inputs to the development of evidence for health policy

Valid, reliable and comparable measures of the health states of individuals and of the health status of populations are critical components of the evidence base for health policy. We need to develop population health measurement strategies that coherently address the relationships between epidemiological measures (such as risk exposures, incidence, and mortality rates) and multi-domain measures of population health status, while ensuring validity and cross-population comparability.     

Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons

Opioids mediate their analgesic effects by activating mu-opioid receptors (MOR) not only within the central nervous system but also on peripheral sensory neurons. The peripheral analgesic effects of opioids are best described under inflammatory conditions (e.g., arthritis). The present study investigated the effects of inflammation on MOR binding and G-protein coupling of full versus partial MOR agonists in dorsal root ganglia (DRG) of primary afferent neurons. Our results show that Freund's complete adjuvant (FCA) unilateral hindpaw inflammation induces a significant up-regulation of MOR binding sites (25 to 47 fmol/mg of protein) on DRG membranes without affecting the affinity of either full or partial MOR agonists. In our immunohistochemical studies, the number of MOR-immunoreactive neurons consistently increased. This increase was mostly caused by small-diameter nociceptive DRG neurons. The full agonist DAMGO induced MOR G-protein coupling in DRG of animals without FCA inflammation (EC50 = 56 nM; relative Emax = 100%). FCA inflammation resulted in significant increases in DAMGO-induced MOR G-protein coupling (EC50 = 29 nM; relative Emax = 145%). The partial agonist buprenorphine hydrochloride (BUP) showed no detectable G-protein coupling in DRG of animals without FCA inflammation; however, partial agonist activity of BUP-induced MOR G-protein coupling was detectable in animals with FCA inflammation (EC50 = 1.6 nM; relative Emax = 82%). In behavioral studies, administration of BUP produced significant antinociception only in inflamed but not in noninflamed paws. These findings show that inflammation causes changes in MOR binding and G-protein coupling in primary afferent neurons. They further underscore the important differences in clinical studies testing peripherally active opioids in inflammatory painful conditions.