Peripheral opioid analgesia: Clinical applications

Peripheral opioid analgesia is undoubtedly of clinical relevance, especially considering that systemic opioid therapy often is hampered by central side effects. Despite some clinical studies that do not show peripheral opioid-mediated pain control, mostly because of methodologic shortcomings, studies evaluating inflammatory pain conditions show clear evidence and the number and the sites of applications are increasing. The intention of this paper is to give insight into the recent experience with the clinical applications of peripheral opioid analgesia.     

Gender effects and central opioid analgesia.

Central morphine analgesia is significantly greater in male than in female rats. Since mu and delta opioid receptor subtypes have been implicated in supraspinal analgesia, the present study evaluated whether gender or adult gonadectomy altered (a) analgesia on the tail-flick and jump tests following central administration of the mu-selective agonist, [D-Ala2, Me-Phe4, Gly(ol)5] enkephalin (DAMGO) and the delta-selective agonist, [D-Ser2,Leu5] enkephalin-Thr6 (DSLET) and (b) mu1, mu2 and delta opioid receptor binding. Sham-operated male rats displayed significantly greater magnitudes of peak and total analgesia than sham-operated females on the tail-flick test following DAMGO, but not DSLET. Gender differences were not observed for DAMGO and DSLET analgesia on the jump test. Gonadectomy failed to consistently affect either DAMGO or DSLET analgesia. Regression analyses failed to reflect significant shifts in the dose-response functions for either agonist on either measure. Gender differences were not observed for mu1, mu2, or delta binding in hypothalamus or cortex. These data are compared with analgesic responses sensitive to gender differences.     

Epidural opioid analgesia

Epidural opioid analgesia has become an important therapeutic technique in the management of acute pain and has been demonstrated to be superior or equal to other parenteral opioid techniques (intramuscular, intravenous, PCA) with less associated sedation and significantly smaller doses of drugs. Beneficial therapeutic effects of epidural opioids as a result of improved analgesia include improvement in pulmonary function, modification of the endocrine-metabolic stress response, improvement in time to ambulation, decreased morbidity, and shorter hospital stay. The epidural administration of opioids is associated with potential side effects and complications, the most serious potential side effect being that of respiratory depression. This, as well as most of the other potential medication-related side effects associated with epidural opioid analgesia, is for the most part also associated with opioid analgesia provided by other routes of administration. These potential problems either occur rarely, or are controllable or preventable with appropriate patient selection and management. The potential benefits to the critical care patient as a result of the superior analgesia and reduced systemic effects associated with epidural opioid analgesia represent distinct medical and economic advantages, compared to conventional analgesic techniques.     

Long acting local anesthetic-polymer formulation to prolong the effect of analgesia.

Prolonged postoperative analgesia cannot be achieved using single injections of local anesthetic solutions. The study objective was to evaluate the efficacy and toxicity of a new formulation of bupivacaine loaded in an injectable fatty acid based biodegradable polymer poly(sebacic-co-ricinoleic acid) for producing motor and sensory block when injected near the sciatic nerve. Bupivacaine was dissolved in poly(fatty ester-anhydride) paste and tested for drug release in vitro and in vivo after injection in mice. The efficacy and toxicity of the polymer-drug combination was determined by injecting the polymer formulation near the sciatic nerve of mice and measure the sensory and motor nerve blockade for 48 h, while monitoring the animal general health and the injection site. Seventy percent of the incorporated drug was released during 1 week in vitro. Single injection of 10% bupivacaine in the polymer caused motor and sensory block that lasted 30 h. Microscopic examination of the injection sites revealed only mild infiltration in three of eight examined tissues with no pathological findings for internal organs were found. In conclusion the polymer poly(sebacic-co-ricinoleic acid) is a safe carrier for prolonged activity of bupivacaine.     

镁辅助阿片类药物对术后患者镇痛效果的研究进展

正术后疼痛是人体受到手术伤害刺激后的一种反应,不利于患者内环境的稳定,降低患者免疫力。研究~([1])显示,有41%的患者在复苏室,30%的患者在术后第1天,19%的患者在术后第2天经历了中度到重度疼痛,联合应用现有的技术以及多模式镇痛是患者术后镇痛的最佳方式~([2])。多模式镇痛是指通过联合多种作用机制的镇痛药物和不同镇痛方法,阻断疼痛病理生理机制的不同时相和靶位,削减外周和中枢敏感度,进而促使其治疗效果最大化~([3])。     

Sex differences in opioid analgesia: clinical and experimental findings.

Sex differences in analgesic responses to opioids have received increasing attention in recent years. This article examines the literature on sex differences in opioid analgesia, including the results of studies from the authors' own laboratories. In general, nonhuman animal studies suggest more robust opioid analgesic responses in males relative to females; however, the human studies completed to date seem to indicate greater opioid analgesia among females. The most consistent evidence of sex differences in analgesia comes from studies of kappa-agonist-antagonists administered to patients following oral surgery. These data indicate more robust analgesia in females, and dose-response characteristics suggest that these agents possess both analgesic and antianalgesic properties, and the agonists may produce these effects in different proportions for women versus men. In contrast, the data from laboratory pain models in humans suggest greater analgesic effects in women in response mu-opioid agonists but not kappa-agonist-antagonists. Multiple mechanisms may explain sex differences in opioid analgesia, including gonadal hormonal effects, pharmacokinetics and pharmacodynamics, genetic influences, balance of analgesic/antianalgesic processes, and psychological factors. However, the disparity of results obtained from different pain models--animals versus humans and clinical pain versus experimental pain in humans--suggests that the models themselves are mechanistically different. Additional investigation is warranted in order to further explicate the nature of sex differences in opioid analgesia and to elucidate the underlying mechanisms.     

Involvement of cytokines, chemokines and adhesion molecules in opioid analgesia.

Tissue destruction is accompanied by an inflammatory reaction. The inflammatory reaction leads to activation of nociceptors and the sensation of pain. Several mediators are responsible for pain and hyperalgesia in inflammation including cytokines, chemokines, nerve growth factor as well as bradykinin, prostaglandins and ATP. Simulatenously however, analgesic mediators are secreted: opioid peptides, somatostatin, endocannabinoids and certain cytokines. Opioid peptides secreted from immune cells are so far the best studied peptides in peripheral inflammatory pain control. This system is hampered for example by anti-adhesion molecule treatment. Novel immunosuppressive drugs for treatment of autoimmune disease targetting cytokines, chemokines or adhesion molecules should therefore be evaluated for potential harmful effects on pain.     

Potential applications and significance of peripheral opioid analgesia

Recently, the local application of analgesic substances has attracted much interest and has become increasingly relevant in daily clinical practice. The lack of the well-known therapy-limiting central side effects of systemically administered opioids is a clear advantage of "peripheral opioid analgesia". Important prerequisites for the occurrence of peripheral analgesic effects of opioids are good accessibility of the painful site, presence of clinically relevant pain, signs of a local inflammation, exclusion of a fast systemic absorption, and adequately potent analgesic substances. This review gives an outline of recent experience with various clinical applications of "peripheral opioid analgesia".     

The effect of opioid analgesia on exercise test performance in chronic low back pain

The effect of opioid analgesia on tests of muscular function in chronic low back pain (CLBP) is unknown. Twenty-eight subjects with CLBP of at least moderate intensity performed the Sorensen isokinetic exercise test once after receiving 1 microg/kg fentanyl intravenously and once after placebo in a randomized-order double-blind crossover design. Naloxone 3 microg/kg was administered after the fentanyl phase. Fentanyl reduced mean+/-SD pain from 4.0+/-2.1 to 3.1+/-2.2 on a 0-10 verbal rating scale (P<0.05). Mean+/-SD Sorensen test performance was 77+/-49 s in the fentanyl arm and 60+/-42 s in the placebo arm. This represents an increased performance with fentanyl of 28% (P<0.001). We conclude that in addition to relieving pain in CLBP, the administration of 1 microg/kg fentanyl is associated with an improvement in lumbar exercise test performance. We presume that the pain relief resulted in increased test performance. Our result is at odds with those of randomized trials which have failed to demonstrate increased function following the treatment of pain with opioid analgesics. This highlights the complexity of the interaction between pain, analgesia and changes in function.     

Epidural opioid analgesia in infant rats I: mechanical and heat responses.

The aim of this study was to investigate the analgesic effects of epidural opioids in neonatal rat pups. The contribution of individual opioid receptor subtypes in the spinal cord to analgesia at different developmental stages was investigated using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged postnatal day (P) 3, 10 and 21. Thresholds for flexion withdrawal reflexes to mechanical stimuli (von Frey hairs) and to noxious heating of the hind paw were low in neonates and increased with postnatal age. The analgesic action of each opioid receptor agonist followed an individual developmental pattern. In mechanical tests, all three opioid agonists were considerably more efficacious analgesics in younger animals and ED50s at P3 were always lower than at P21. In heat tests, the pattern differed. The efficacy of the kappa opioid agonist decreased with postnatal age, morphine efficacy increased over the same period and the effects of the delta agonist remained relatively unchanged. The distribution and concentration of tritiated morphine in the spinal cord following epidural administration did not alter significantly with postnatal age, suggesting that opioid access is not a major determinant of the effects reported here. It is concluded that whereas heat pain is particularly sensitive to spinal kappa opioids in neonates, mechanical sensory thresholds are generally sensitive to all spinal opioids in the newborn. The differing epidural opioid requirements compared to older subjects is likely to be due to developmental changes in spinal cord opioid receptor distribution or pharmacology.     

Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors

The tolerance effects of continuous intrathecal infusions of opioids at mu and delta receptors were studied in rats. These effects were compared to those of chronic systemic morphine. A chronic intrathecal infusion of the relatively selective delta agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), produced a larger degree of tolerance to DADLE than to the highly specific mu-activating morphiceptin analog [N-methyl-Phe3, D-Pro4]morphiceptin (PL017). The slope of the analgesic dose-response curve for the highly specific delta agonist, cyclic [D-Penicillamine2, D-Penicillamine5]enkephalin (DPDPE), was significantly different (flatter) from those of mu agonists or DADLE. High-dose infusion of PL017 induced a 61-fold parallel shift of the dose-response curve for PL017. This same treatment also induced a corresponding flattened, nonparallel change of the dose-response curve for DADLE. This altered curve for DADLE was very similar in slope to that of DPDPE. Pretreatment with the irreversible mu antagonist, beta-funaltrexamine, caused a parallel rightward shift of the dose-response curve for PL017 but did not affect DPDPE activity. beta-Funaltrexamine treatment induced a nonparallel rightward shift of the dose-response curve for DADLE with a change of slope similar to that of DPDPE. These findings demonstrate a mixed mu-delta analgesic activity for the compound DADLE, which is often referred to as a prototypic delta agonist. These interactions differ from prior reports of none or minimal mu-ligand interactions with DADLE. Despite the cross-reactivity of DADLE to mu receptors, DADLE remains a more effective analgesic than do mu agonists in states of mu receptor tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Patient and physician agreement on abdominal pain severity and need for opioid analgesia.

Whereas controversy surrounds emergency department (ED) analgesia administration to patients with undifferentiated abdominal pain, few studies have addressed the level of patient-physician agreement on abdominal pain severity and need for opioid analgesia. This prospective study was undertaken to assess concordance between emergency physicians and patients on abdominal pain severity. Study subjects were a convenience sample of 30 adults seen in an urban university-affiliated tertiary care ED (annual census 65,000) who had undifferentiated abdominal pain meeting an initial severity threshold of 5 on a 10 cm visual analog scale (VAS) marked by the patient. Patients' and physicians' VAS scores, obtained in blinded fashion at presentation (t0) and at one (t1) and two (t2) hours into the ED stay, were compared with t test (VAS scores) and sign-rank (percent change in VAS scores) analyses. In addition, patients and physicians were asked at each assessment time, in blinded fashion, "Is the pain severe enough to warrant morphine?" The kappa statistic was used to characterize the degree of agreement between physician and patient assessments as to whether opioids were indicated. At t0, t1, and t2, patients' mean VAS scores (7.5, 6.7, and 5.1) were significantly (P < .05) higher than the corresponding physicians' VAS scores (5.3, 4.7, and 3.9). Though VAS scores for physicians started lower than those of patients, the percentage changes in scores from one assessment to the next were similar by Wilcoxon sign-rank testing (P > .50 for time intervals t0 - t1 and t1 - t2). Overall, patients and physicians agreed on the question of whether pain was sufficient to warrant opioids in 71 of 90 (78.9%) assessments; the corresponding kappa statistic of .57 indicated moderate agreement (P < .0001). These results, indicating that patients and physicians usually agree on whether opioids are warranted for abdominal pain, have important implications for further research on ED analgesia in this population.     

Kappa opioid analgesia is dependent on serotonergic mechanisms

The serotonergic dependence of mu and kappa opioid analgesia was compared in the mouse tail-flick and hot-plate assays using morphine and the selective kappa agonist, U-50, 488H, respectively. Depletion of serotonin with p-chlorophenylalanine resulted in a marked antagonism of U-50,488H analgesic potency in both assays, as did reserpine pretreatment. Both of these effects were dose-related and the latter was reversed by treatment with the serotonin precursor, 5-hydroxytryptophan. Several reputed serotonin antagonists (cyproheptadine, ketanserin and pirenperone) also antagonized U-50,488H analgesia. In contrast, the analgesic potency of morphine was only decreased slightly by p-chlorophenylalanine and reserpine, and not at all by the serotonin antagonists. Thus, kappa, but not mu, analgesia is strongly dependent upon serotonergic mechanisms in these assays. However 5-hydroxytryptophan did not enhance U-50,488H analgesia in nonpretreated mice or in mice made tolerant to U-50,488H. Likewise, it did not alter the development of U-50,488H tolerance. On this basis it appears that kappa opioid tolerance is not due to serotonergic hypofunction.     

Epidural opioid analgesia in infant rats II: responses to carrageenan and capsaicin.

The aim of this study was to investigate the analgesic effects of epidural opioids upon persistent pain sensitivity in neonatal rat pups. Two models of persistent pain were used, subcutaneous injection of carrageenan, and topical application of capsaicin cream, both to the hind paw. The contribution of individual opioid receptor subtypes in the spinal cord to analgesia were tested at different developmental stages using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged P (postnatal day) 3, 10 and 21. Rat pups at all three ages displayed a reduction in mechanical (von Frey hair) threshold following carrageenan-induced inflammation of the hind paw that was evident at 3 h and was still present 5 h after application. This effect was greatest in magnitude at P21. This response was blocked by low doses of all three agonists at all ages, relative effectiveness varying with age. Comparison with potencies in acute tests (Marsh, D., Dickenson, A., Hatch, D. and Fitzgerald, M., Epidural opioid analgesia in infant rats I: mechanical and heat responses, Pain 82 (1999) 23-32) show that opioid potency is significantly greater in the presence of carrageenan inflammation at all ages. Topical capsaicin application to the hind paw produced a significant fall in withdrawal latencies to noxious heat. Generally, epidural opioid agonists did not block this C-fibre induced sensitization except at P3, when morphine and DPDPE did prevent the fall in threshold in a dose dependent manner. The results show that newborn rat pups are capable of displaying both allodynia and hyperalgesia following experimental inflammation that is blocked by epidural mu, delta and kappa opioids. The opioid potency is enhanced compared with antinociception in acute tests. This is not observed following capsaicin hyperalgesia and is therefore not a general consequence of C fibre induced increases in central excitability but relies upon mechanisms special to inflammatory pain.