Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study.

There is accumulating evidence that opioid therapy might not only be associated with the development of tolerance but also with an increased sensitivity to pain, a condition referred to as opioid-induced hyperalgesia (OIH). However, there are no prospective studies documenting the development of opioid tolerance or OIH in patients with chronic pain. This preliminary study in 6 patients with chronic low back pain prospectively evaluated the development of tolerance and OIH. Patients were assessed before and 1 month after initiating oral morphine therapy. The cold pressor test and experimental heat pain were used to measure pain sensitivity before and during a target-controlled infusion with the short-acting mu opioid agonist remifentanil. In the cold pressor test, all patients became hyperalgesic as well as tolerant after 1 month of oral morphine therapy. In a model of heat pain, patients exhibited no hyperalgesia, although tolerance could not be evaluated. These results provide the first prospective evidence for the development of analgesic tolerance and OIH by using experimental pain in patients with chronic back pain. This study also validated methodology for prospectively studying these phenomena in larger populations of pain patients. PERSPECTIVE: Experimental evidence suggests that opioid tolerance and opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain. This study validates a pharmacologic approach to study these phenomena prospectively in chronic pain patients and suggests that both conditions do occur within 1 month of initiating opioid therapy.     

Modulation of remifentanil-induced postinfusion hyperalgesia by the β-blocker propranolol in humans

Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the β(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the β-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. β-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.     

Molecular distinction of three N-methyl-D-aspartate-receptor subtypes in situ and developmental receptor maturation demonstrated with the photoaffinity ligand 125I-labeled CGP 55802A.

Activation of N-methyl-D-aspartate (NMDA) receptors is essential for synaptic plasticity in the central nervous system and contributes to neuronal death under various pathological conditions. Although several subunits have been cloned, the structure of NMDA receptors in situ is unresolved. By using a photoreactive antagonist with nanomolar affinity to the NMDA-binding site, three types of receptors were differentiated by their pattern of photoaffinity-labeled subunits. In adult brain, a protein of 175-kDa was photoreactive that displayed a profile of ligand binding and autoradiographical distribution corresponding to NMDA receptors. In contrast, in early postnatal brain, proteins of both 175 kDa and 115 kDa were photolabeled. This labeling pattern is switched to that of adult brain around postnatal day 10, pointing to a structural maturation of NMDA receptors. A third type of receptor could be identified in cerebellar granule cell cultures, where NMDA receptors mediate trophic effects and photolabeling was exclusively targeted to a 115-kDa protein. To identify the proteins labeled in situ, recombinant receptors were subjected to photolabeling. When the NR1 subunit was coexpressed with either the NR2A, NR2B, or NR2C subunit, only the combination of NR1/NR2A was photoreactive. Both the NR1 and NR2A subunits were photolabeled, corresponding in size to the proteins labeled in situ. However, the lack of subunit-selectivity in photolabeling the NR1/NR2A combination suggests the presence of additional receptor components in situ to explain the subunit-selective photoreactivity in adult brain (175 kDa) and in cerebellar granule cells (115 kDa). The subunit combination NR1/NR2A by itself appears insufficient to describe a major population of NMDA receptors, in particular, in adult brain.     

Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities

OBJECTIVE: To discuss the concepts of the minimal clinically important difference (MCID) and the smallest detectable difference (SDD) and to examine their relation to required sample sizes for future studies using concrete data of the condition-specific Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the generic Medical Outcomes Study 36-Item Short Form (SF-36) in patients with osteoarthritis of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention. METHODS: SDD and MCID were determined in a prospective study of 122 patients before a comprehensive inpatient rehabilitation intervention and at the 3-month followup. MCID was assessed by the transition method. Required SDD and sample sizes were determined by applying normal approximation and taking into account the calculation of power. RESULTS: In the WOMAC sections the SDD and MCID ranged from 0.51 to 1.33 points (scale 0 to 10), and in the SF-36 sections the SDD and MCID ranged from 2.0 to 7.8 points (scale 0 to 100). Both questionnaires showed 2 moderately responsive sections that led to required sample sizes of 40 to 325 per treatment arm for a clinical study with unpaired data or total for paired followup data. CONCLUSION: In rehabilitation intervention, effects larger than 12% of baseline score (6% of maximal score) can be attained and detected as MCID by the transition method in both the WOMAC and the SF-36. Effects of this size lead to reasonable sample sizes for future studies lying below n = 300. The same holds true for moderately responsive questionnaire sections with effect sizes higher than 0.25. When designing studies, assumed effects below the MCID may be detectable but are clinically meaningless.     

Asthma and body weight change: a 20-year prospective community study of young adults

OBJECTIVE: There is increasing evidence for an association between asthma and body weight change. The objectives of these analyses were to examine the temporal relationships of this association and to explore the role of childhood depression as an explanatory factor. METHODS: Data were derived from six subsequent semistructured interviews on health habits and health conditions from a single-age community study of 591 young adults followed up between ages 20 and 40 years. RESULTS: Cross-sectionally (over the whole study period), asthma was significantly associated with obesity (odds ratio=3.9 [95% confidence interval 1.2, 12.2]). Multivariate longitudinal analyses revealed that asthma was associated with increased later weight gain and later obesity among women after controlling for potentially confounding variables, whereas weight gain and obesity were not associated with later asthma. A secondary analysis showed that depressive symptoms during childhood were associated with adult obesity and asthma, partially explaining the asthma-obesity comorbidity. CONCLUSION: This study encourages further research on mechanisms underlying the asthma-obesity comorbidity, particularly on shared psychosocial factors operating during critical periods in childhood and adolescence that may influence the development and persistence of both obesity and asthma during adulthood.     

Inpatient rehabilitation for hip or knee osteoarthritis: 2 year follow up study

OBJECTIVE: To examine the course of pain, physical function, and other health dimensions after a comprehensive inpatient rehabilitation intervention in patients with osteoarthritis (OA) of the hip or knee. METHODS: An observational, prospective cohort study with assessments at baseline (entry into clinic), 1 (discharge from inpatient rehabilitation), 3, 6, 9, 12, and 24 months after baseline. Consecutively referred patients to an inpatient rehabilitation centre fulfilling the inclusion criteria were studied. 3-4 week comprehensive rehabilitation intervention, including strengthening exercise, flexibility training, endurance training, relaxation strategies, and consultations for preventive measures, was carried out. Individual home rehabilitation programmes were taught. Generic health status was measured using the SF-36, condition specific health was measured with the WOMAC questionnaire. Effects were analysed with sensitivity statistics (effect size, ES) and non-parametric tests. RESULTS: Data from 128 patients with complete follow up data were analysed. Both pain and physical function improved moderately (WOMAC pain: ES = 0.56, WOMAC function ES = 0.44) until discharge. Although the effect in pain reduction remained significant by month 24 (WOMAC: ES = 0.26), physical function deteriorated close to baseline values after 12 months. CONCLUSIONS: Comprehensive inpatient rehabilitation of patients with OA of the hip or knee may improve pain and physical function in the mid-term, and pain in the long term.     

The Zurich study

In a longitudinal cohort study of young adults from the Canton of Zurich in Switzerland (Zurich Study), seasonal patterns of several psychiatric and psychosomatic syndromes were investigated in two interviews over a period of three years. At an age of 27-28 years, 23% of the depressives, 15% of the neurasthenic subjects, and 14% of the subjects with backache reported an increased susceptibility in autumn and/or winter. With respect to the course we found that 10.4% of the subjects of the longitudinal sample (n = 417) suffered from seasonal depression (including individuals with subsyndromal seasonal difficulties) over two consecutive years. Specific symptoms, such as hypersomnia, increase of appetite or weight gain, were not found to be consistently associated with seasonal depression. A comparison of actual and retrospective reports on seasonal depression resulted in a very low reliability. In view of these results the seasonal subtype of depression should be diagnosed with caution, except when the diagnosis is based on longitudinal observations and/or external sources of information (e.g. family members, partner).     

A new bipolar spectrum concept: a brief review

Angst J, Gamma A. A new bipolar spectrum concept: a brief review. Bipolar Disord 2002: 4(Suppl. 1): 11–14. © Blackwell Munksgaard, 2002
Research on the broad bipolar spectrum is dependent on the definition of hypomania. We recently proposed a new, softer syndromal definition with clinical validity. This broadens the diagnosis of bipolar II (BP-II) disorder at the expense of major depressive disorder (MDD). There is evidence for a third group of suspected BP-II manifesting major depression plus hypomanic symptoms. The two bipolar-II groups together are as prevalent as MDD. A new concept of minor bipolar disorder embracing dysthymia, minor and recurrent brief depression with hypomanic syndromes and symptoms is discussed. Some methodological pitfalls of research on drug-induced hypomania as an element of the bipolar spectrum are also summarized.