多瑞吉在带状疱疹疼痛治疗阿片类药物转换中的应用

目的:探讨多瑞吉在带状疱疹疼痛治疗阿片类药物转换中的应用。方法:选择37例住院治疗的带状疱疹疼痛患者,年龄>45岁、VAS评分≥4分、所有病人常规抗病毒治疗、增加免疫力等常规治疗,予硬膜外腔置管间断注入消炎镇痛药物并持续泵吗啡,根据疼痛调整至止痛剂量,转换为多瑞吉贴剂后出院。疼痛控制后逐渐减药,每半个月减量半贴多瑞吉,对病人的疼痛评分、生活质量及并发症进行评估。结果:有1例病人应药物副反应出组,其余病人硬膜外泵吗啡后均在一周左右控制疼痛,等效转换为多瑞吉,定时定量减药,无疼痛反复,成瘾戒断等情况。结论:带状疱疹疼痛采用硬膜外间断注药持续泵吗啡迅速达到无痛后,转换为等效剂量的多瑞吉,定时定量减药,安全有效。     

Postoperative pain management in patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis: a narrative review

Posterior spinal fusion for adolescent idiopathic scoliosis is one of the most invasive surgical procedures performed in children and adolescents. Because of the extensive surgical incision and massive tissue trauma, posterior spinal fusion causes severe postoperative pain. Intravenous patient-controlled analgesia with opioids has been the mainstay of postoperative pain management in these patients. However, the use of systemic opioids is sometimes limited by opioid-related side effects, resulting in poor analgesia. To improve pain management while reducing opioid consumption and opioid-related complications, concurrent use of analgesics and analgesic modalities with different mechanisms of action seems to be rational. The efficacy of intrathecal opioids and nonsteroidal anti-inflammatory drugs as components of multimodal analgesia in scoliosis surgery has been well established. However, there is either controversy or insufficient evidence regarding the use of other analgesic methods, such as continuous ketamine infusion, perioperative oral gabapentin, acetaminophen, continuous wound infiltration of local anesthetics, a single dose of systemic dexamethasone, and lidocaine infusion in this patient population. Moreover, appropriate combinations of analgesics have not been established. The aim of this literature review is to provide detailed information of each analgesic technique so that clinicians can make appropriate choices regarding pain management in patients with adolescent idiopathic scoliosis undergoing posterior spinal fusion.     

Possible Role of Laxatives in Analgesic Nephropathy

Eight out of ten of patients with analgesic nephropathy were regular and usually heavy laxative takers compared with 12 out of 200 controls from the general population and four out of 70 patients attending a renal clinic. The finding that regular laxative taking was greatly increased in patients with analgesic nephropathy suggests that this condition may often be due to the combined abuse of both laxatives and analgesics. In a series of 40 patients with rheumatoid arthritis all were found to have normal renal function and no patient took laxatives regularly. This finding would explain why analgesic nephropathy is so uncommon in patients with rheumatoid arthritis despite the fact that they are regular and heavy analgesic takers.     

The doctor's dilemma: opiate analgesics and chronic pain

Opiates are utilized routinely and effectively as a short-term analgesic treatment for a variety of acute pain conditions such as occur following trauma, and for patients with painful terminal diseases such as cancer. Because opiate analgesics are highly addictive substances, their use in the treatment of chronic nonmalignant pain remains controversial.     

Anaesthesia and post-operative analgesia following experimental surgery in laboratory rodents: are we making progress?

Current attitudes to the use of animals in biomedical research require that any pain or distress should be minimised. This can often be achieved by the use of appropriate anaesthetic and analgesic regimens. There, is however, little information on the peri-operative regimens used. A literature review was conducted to estimate how commonly analgesics are administered to laboratory rodents, the most widely used species of laboratory animals, and to assess the anaesthetic regimens employed. Studies describing potentially painful experimental procedures involving rodents were identified from peer-reviewed journals published from 1990 to 1992 and from 2000 to 2002. In papers published between 2000 and 2002, if analgesic administration was not specified, the institutional veterinary surgeons or authors of the papers were contacted by e-mail to obtain additional information on analgesic use. From 1992 to 2002, there was an increase in the reported prevalence of analgesic administration to laboratory rodents from 2.7% to 19.8%. Although the use of analgesics has increased over the past ten years, the overall level of post-operative pain relief for laboratory rodents is still low. Anaesthetic methodology changed markedly between the two time-periods sampled. Notably, there was an increase in the use of isoflurane and of injectable anaesthetic combinations such as ketamine/xylazine, whereas the use of ether and methoxyflurane decreased.     

Comparative Analgesic Activity of Levomepromazine and Morphine in Patients with Chronic Pain

Apart from its ability to potentiate the action of narcotics, levomepromazine, a phenothiazine derivative, was shown to possess its own analgesic activity comparable to that of morphine at a 3:2 dose relationship.In a double-blind crossover study of 18 patients suffering from chronic pain (cancer and arthritis), levomepromazine (15 mg.) was compared with morphine (10 mg.) and placebo. Three hours after intramuscular administration, levomepromazine proved to be significantly superior to placebo (p < .05) and indistinguishable from morphine. Evaluations of pain relief by estimations of changes in pain intensity were found to correlate well with evaluations based on recognition of pain relief exceeding 50%.The potent analgesic effect of levomepromazine was obtained at the price of excessive sedation. This, however, was considered an acceptable side effect in a patient suffering from chronic pain. These results provide encouragement in the quest for a non-addicting substitute for morphine.     

Association between KCNJ6 (GIRK2) Gene Polymorphisms and Postoperative Analgesic Requirements after Major Abdominal Surgery

Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioid analgesics. We focused on a G-protein-activated inwardly rectifying potassium (GIRK) channel subunit, GIRK2, that is an important molecule in opioid transmission. In our initial polymorphism search, a total of nine single-nucleotide polymorphisms (SNPs) were identified in the whole exon, 5′-flanking, and exon-intron boundary regions of the KCNJ6 gene encoding GIRK2. Among them, G-1250A and A1032G were selected as representative SNPs for further association studies. In an association study of 129 subjects who underwent major open abdominal surgery, the A/A genotype in the A1032G SNP and -1250G/1032A haplotype were significantly associated with increased postoperative analgesic requirements compared with other genotypes and haplotypes. The total dose (mean±SEM) of rescue analgesics converted to equivalent oral morphine doses was 20.45±9.27 mg, 10.84±2.24 mg, and 13.07±2.39 mg for the A/A, A/G, and G/G genotypes in the A1032G SNP, respectively. Additionally, KCNJ6 gene expression levels in the 1032A/A subjects were significantly decreased compared with the 1032A/G and 1032G/G subjects in a real-time quantitative PCR analysis using human brain tissues, suggesting that the 1032A/A subjects required more analgesics because of lower KCNJ6 gene expression levels and consequently insufficient analgesic effects. The results indicate that the A1032G SNP and G-1250A/A1032G haplotype could serve as markers that predict increased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.     

Consequences associated with nonnarcotic analgesics in the fetus and newborn

Nonnarcotic analgesics include well-known, widely used substances such as acetylsalicylic acid (ASA) and acetaminophen. ASA is a potent inhibitor of prostaglandin synthesis, and this mechanism is responsible for many potential toxicities in the fetus and newborn. These may include bleeding, altered renal function, and constriction of the ductus arteriosus in addition to analgesia. As such, ASA is frequently avoided during gestation and the immediate neonatal period. Acetaminophen is less well recognized as an agent with activity outside the central nervous system. It does not possess antiinflammatory activity like other substances that inhibit prostaglandins but has been shown to be an analgesic with potency comparable to ASA. This is believed to be by inhibition of brain prostaglandin synthetase. We have determined by using the chronically catheterized sheep fetus that acetaminophen has potent activity on the ductus arteriosus and produces a constriction, in therapeutic analgesic quantities, comparable to ASA. Thus, acetaminophen may be a potent inhibitor of prostaglandin function in the fetus.     

The Conditioned Place Preference Test for Assessing Welfare Consequences and Potential Refinements in a Mouse Bladder Cancer Model

Most pre-clinical analgesic efficacy assays still involve nociceptive testing in rodents. This is despite concerns as to the relevance of these tests for evaluating the pain-preventative properties of drugs. More appropriate methods would target pain rather than nociception, but these are currently not available, so it remains unknown whether animal pain equates to the negatively affective and subjective/emotional state it causes in humans. Mouse cancer models are common despite the likelihood of substantial pain. We used Conditioned Place Preference (CPP) testing, assessments of thermal hyperalgesia and behaviour to determine the likelihood that MBT-2 bladder cancer impacts negatively on mouse welfare, such as by causing pain. There was no CPP to saline, but morphine preference in tumour bearing mice exceeded that seen in tumour-free controls. This occurred up to 10 days before the study end-point alongside reduced body weight, development of hyperalgesia and behaviour changes. These effects indicated mice experienced a negative welfare state caused by malaise (if not pain) before euthanasia. Due to the complexity of the assessments needed to demonstrate this, it is unlikely that this approach could be used for routine welfare assessment on a study-by-study basis. However, our results show mice in sufficiently similar studies are likely to benefit from more intensive severity assessment and re-evaluation of end-points with a view to implementing appropriate refinements. In this particular case, a refinement would have been to have euthanased mice at least 7 days earlier or possibly by provision of end-stage pain relief. CPP testing was found to be a helpful method to investigate the responses of mice to analgesics, possibly on a subjective level. These findings and those of other recent studies show it could be a valuable method of screening candidate analgesics for efficacy against cancer pain and possibly other pain or disease models.     

Postoperative analgesia: a comparison of intravenous on-demand fentanyl with epidural bupivacaine.

In a randomised trial postoperative pain relief was provided by either epidural injections of bupivacaine or an infusion of fentanyl adjusted by the patient to achieve adequate pain relief. Both techniques produced satisfactory analgesia without respiratory depression after peripheral arterial surgery. The technique of infusing intravenously a potent analgesic in a dose adjusted by the patient appears to offer several advantages in postoperative care.     

Enzymatic degradation of endomorphins

Centrally acting plant opiates, such as morphine, are the most frequently used analgesics for the relief of severe pain, even though their undesired side effects are serious limitation to their usefulness. The search for new therapeutics that could replace morphine has been mainly focused on the development of peptide analogs or peptidomimetics with high selectivity for one receptor type and high bioavailability, that is good blood-brain barrier permeability and enzymatic stability. Drugs, in order to be effective, must be able to reach the target tissue and to remain metabolically stable to produce the desired effects. The study of naturally occurring peptides provides a rational and powerful approach in the design of peptide therapeutics. Endogenous opioid peptides, endomorphin-1 and endomorphin-2, are two potent and highly selective mu-opioid receptor agonists, discovered only a decade ago, which display potent analgesic activity. However, extensive studies on the possible use of endomorphins as analgesics instead of morphine met with failure due to their instability. This review deals with the recent investigations that allowed determine degradation pathways of endomorphins in vitro and in vivo and propose modifications that will lead to more stable analogs.     

Behavioral control of the efficiency of pharmacological anesthesia in fish

An original behavioral test was used to study the effect of opioid substances on the thresholds of nociceptive responses to pain stimuli—a series of electric impulses applied to nerve endings of the caudal fin—in the common carp (Cyprinus carpio). The substances tested included tramadol (μ-agonist of opioid receptors), DADLE (δ-agonist), and U-50488 (κ-agonist) injected intramuscularly in concentrations 10–100 nmol/g of body weight. Raised thresholds of sensitivity to the pain stimulus were observed in the studied fish 5 to 15 min after the injection. The degree of analgesia and the rate of its increase varied depending on the dose. The total duration of analgesia was 40 to 90 min and depended on the concentration of the injected substance. It was observed in some experiments that the analgesic effect of tramadol (the most efficient of the analgesics used) could last longer than 4 h. The analgesic effect of opioids was not detected in experiments where they were applied together with naloxone, an antagonist of opioids. Decreased motor response to pain stimuli after injections of analgesics was not caused by the immobilization of the animal, because the tested fish individuals released into an aquarium demonstrated normal swimming and their usual behavior. We concluded that the systems of opioid nociceptive regulation function similarly in fish and land vertebrates. This regulation can play an important role in defense behavior and in other behaviors in fish.     

Structure-activity relationship of the novel bivalent and C-terminal modified analogues of endomorphin-2

Endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2)) is a putative endogenous mu-opioid receptor ligand. To develop potent analgesics with less side effects related to it, we used the methods of dimerization and C-terminal modification. Through dimerization we got the 'balanced agonists' with potent analgesic activity and we have developed the structure-activity relationship between the selectivity and the distance of the two tyrosine pharmacophores. Modification at the C-terminal increased the selectivity of endomorphin-2 to mu-opioid receptor with binding affinity conserved.     

Analgesic activity of double endorphins in vivo

The effects of double endorphins DALA2, DYNO2, CASO2 on pain threshold in the rats were compared with those of DALA (D-Ala2-Met5-enkephalinamide). Marked differences in the analgesic potency of the investigated peptides were noted. The most potent analgesic effect was exerted by DALA2. DYNO2 was weaker than DALA and DALA2 due to lack of glycine residue in position 3, probably responsible for the receptor affinity and analgesic activity in vivo. The weak analgesic activity of CASO2 in vivo corresponds with the weak opiate agonistic action of this peptide in vitro [see 7]. All investigated peptides induced changes in animal behaviour when injected i.c.v. The results indicated that among peptides in the novel group of double endorphins, DALA2 is of special interest because of a potent and long lasting analgesic action.     

Behavioural assessment of the effects of tumour growth in rats and the influence of the analgesics carprofen and meloxicam

Very little is known concerning the occurrence of pain in cancer research models. We wished to establish whether a behaviour-based approach, originally developed to assess postoperative pain, could be used to determine positive effects of the analgesics carprofen and meloxicam in rats that might be experiencing pain during tumour development in an orthotopic model of bladder cancer. An invasive but non-metastatic rat bladder cancer cell line was surgically implanted into the bladder wall of 57 inbred Fisher344 rats. The rats underwent daily clinical assessments. When clinical signs consistent with chronic pain were apparent, behavioural data were collected from 44 animals during 2 x 10 min periods, immediately before and one hour after a subcutaneous injection of either physiological saline (0.9%; 0.2 ml/100 g), carprofen (5 mg/kg) or meloxicam (2 mg/kg). Treatment-associated behaviour changes were then compared between groups. The lack of active behaviour, both before and after each treatment, was consistent with established clinical signs of pain. The rats were so inactive following the treatment that the behavioural technique we had previously developed was of comparatively little use in determining either pain severity or analgesic efficacy. One very prominent effect, however, was an increase in ventral abdominal licking in the control (saline) group. As this was absent in rats given meloxicam or carprofen, and has previously been considered to indicate pain emanating from damaged tissue, it was concluded that the analgesic-treated rats gained at least some benefit from the drug treatments, but it was not possible to gauge the extent of this. Handling for examination or treatment may have intensified pain in rats in the control group, and so this should be avoided whenever possible. It is likely that post-surgical pain differs markedly from cancer pain, so a different set of behavioural markers may be needed to assess it effectively. More intensive behaviour monitoring may help to develop a suitable technique for detecting the onset of, and assess the severity of pain that may occur during tumour development.     

Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans

The perception of pain is subject to powerful influences. Understanding how these are mediated at a neuroanatomical and neurobiological level provides us with valuable information that has a direct impact on our ability to harness positive and minimize negative effects therapeutically, as well as optimize clinical trial designs when developing new analgesics. This is particularly relevant for placebo and nocebo effects. New research findings have directly contributed to an increased understanding of how placebo and nocebo effects are produced and what biological and psychological factors influence variances in the magnitude of the effect. The findings have relevance for chronic pain states and other disorders, where abnormal functioning of crucial brain regions might affect analgesic outcome even in the normal therapeutic setting.     

Unique spirocyclopiperazinium salt III: further investigation of monospirocyclopiperazinium (MSPZ) salts as potential analgesics

Two novel classes of monospirocyclopiperazinium salts were designed, synthesized, and evaluated for their in vivo analgesic activities. Some interesting structure-activity relationships are revealed: (1) Spirocyclopiperazinium moiety is favorable to improve the analgesic activity; (2) The size and conformation of spirocyclopiperazinium moiety significantly affects the analgesic activity; (3) Phenylethyl group of 3d is a crucial pharmacophore. Among the compounds synthesized, 3d exhibited the most potent activity with low toxicity. Further antinociceptive mechanism studies of 3d showed that these compounds will be a new kind of analgesics.     

FS 205-397: a new antipyretic analgesic with a paracetamol-like profile of activity but lack of acute hepatotoxicity in mice

FS 205-397 has been designed to mimic or improve the antipyretic/analgesic profile of paracetamol but without inducing hepatic failure. FS 205-397 offers advantages over acetylsalicylic acid since it has caused no gastric lesions in rats and unlike paracetamol it produced no hepatotoxicity in animal models. The antinociceptive potency of FS 205-397 was at least that of acetylsalicylic acid and paracetamol and in some models it was somewhat more potent. FS 205-397 was even active in the hot plate test, a model in which most non-narcotics are inactive. FS 205-397 will offer potent analgesic and antipyretic therapy in man based on an innovative biochemical principle which eliminates the undesirable toxic effects associated with most other non-narcotic analgesics.     

Traumeel S® for pain relief following hallux valgus surgery: a randomized controlled trial

Background

In spite of recent advances in post-operative pain relief, pain following orthopedic surgery remains an ongoing challenge for clinicians. We examined whether a well known and frequently prescribed homeopathic preparation could mitigate post-operative pain.

Method

We performed a randomized, double blind, placebo-controlled trial to evaluate the efficacy of the homeopathic preparation Traumeel S^® in minimizing post-operative pain and analgesic consumption following surgical correction of hallux valgus. Eighty consecutive patients were randomized to receive either Traumeel tablets or an indistinguishable placebo, and took primary and rescue oral analgesics as needed. Maximum numerical pain scores at rest and consumption of oral analgesics were recorded on day of surgery and for 13 days following surgery.

Results

Traumeel was not found superior to placebo in minimizing pain or analgesic consumption over the 14 days of the trial, however a transient reduction in the daily maximum post-operative pain score favoring the Traumeel arm was observed on the day of surgery, a finding supported by a treatment-time interaction test (p = 0.04).

Conclusions

Traumeel was not superior to placebo in minimizing pain or analgesic consumption over the 14 days of the trial. A transient reduction in the daily maximum post-operative pain score on the day of surgery is of questionable clinical importance.

Trial Registration

This study was registered at ClinicalTrials.gov. # NCT00279513