Initial Analgesia Research Articles

Combined epidural clonidine and neostigmine safely and effectively prolong initial spinal labour analgesia: a randomised, double-blind, placebo-controlled trial

Van Dam, N.; Devroe, S.; Decoster, J.; Vandermeersch, E.; Van de Velde, M. Author Information

Patient-controlled Epidural Analgesia following Combined Spinal-epidural Analgesia in Labour: The Effects of Adding a Continuous Epidural Infusion

Patient-controlled epidural analgesia (PCEA) is used to maintain epidural analgesia following initial intrathecal analgesia. This trial investigated whether a continuous background infusion with PCEA provides superior analgesia to PCEA alone among patients who received combined spinal-epidural (CSE) analgesia during labour Eighty parturients were randomized to either PCEA alone (PCEA) or PCEA with a background infusion of ropivacaine 0.15% with sufentanil 0.75 microg/ml at 2 ml/h (PCEA + CEI). PCEA settings were a bolus of 4 ml of the same analgesic solution with a lockout interval of 15 minutes. Significantly more patients in the PCEA group required at least one anaesthetist intervention for breakthrough pain (27 [71%] vs 10 [25%] in the PCEA + CEI group, P<0.05). Consumption of local anaesthetic (excluding manually administered boluses) was similar between the groups. If anaesthetist-administered boluses were included, more local anaesthetic was consumed by the PCEA group (47.1 +/- 19.4 mg vs 35.6 +/- 12.0 mg in the PCEA + CEI group, P<0.05). We conclude that PCEA with a background infusion provides effective analgesia with less anaesthetist workload and reduced local anaesthetic consumption as compared with PCEA without a background infusion.

The Risk of Cesarean Delivery With Neuraxial Analgesia Given Early versus Late in Labor

The recommendation that epidural anesthesia be delayed in nulliparous women until there is 4–5 cm of cervical dilatation rests on an increased risk of cesarean delivery at less than 4.0 cm. It is not clear whether this is a result of the analgesia or other factors. The authors postulated that neuraxial analgesia administered early in labor using intrathecal opioid, as part of a low-dose local anesthetic technique, would not increase the risk of operative delivery. A randomized trial enrolled 728 nulliparous women at term who either were in spontaneous labor or had spontaneous rupture of membranes and whose cervical dilatation was less than 4.0 cm. The participants received either intrathecal fentanyl, with bupivacaine added as needed, or systemic (intravenous and intramuscular) hydromorphone when they first asked for analgesia. Epidural analgesia was started at the second request for analgesia in the intrathecal group, and at cervical dilatation of 4.0 or more, or at the third request for pain relief in the systemic group. Rates of cesarean delivery did not differ significantly between the 2 groups, and there also were no significant differences in the rate of instrumental vaginal delivery or indications for operative delivery. The maximum rate of oxytocin infusion was, however, higher in women given systemic analgesia. Neither type of insurance (private or public) nor different obstetric providers made a difference. Times from initial analgesia to complete dilatation and vaginal delivery were significantly shorter when intrathecal analgesia was used. The intrathecal group had less nausea and vomiting, and neuraxial analgesia lasted longer in this group than in women given systemic analgesia. There was no significant group difference in worrisome fetal heart rate tracings. The findings in this randomized trial indicate that nulliparous women in spontaneous labor, or having spontaneous membrane rupture, may receive neuraxial analgesia early in the course of labor without adverse effects. Early neuraxial analgesia does not appear to increase the number of cesarean deliveries compared with systemic opioid analgesia, and it may shorten labor.

Resting and Evoked Spinal Substance P Release during Chronic Intrathecal Morphine Infusion: Parallels with Tolerance and Dependence

Spinal opiate analgesia is associated with presynaptic inhibition of release of excitatory neurotransmitters/neuromodulators, e.g., substance P (SP), from primary afferent terminals. Chronic intrathecal (i.t.) administration of opiates such as morphine results in an initial analgesia followed by tolerance and a state of dependence. In this study, we examined the resting and evoked neurokinin 1 receptor (NK1r) internalization, indicative of endogenous SP release, in dorsal horn neurons of the lumbar spinal cord by immunocytochemistry during chronic i.t. infusion of morphine in rats. Noxious mechanical stimulation (compression) applied to unilateral hind paw evoked a significant increase in NK1r internalization in lamina I neurons in the ipsilateral dorsal horn. Intrathecal morphine infusion (40 nmol/microl/h) for 1 day possessed similar analgesic efficacy as acute morphine and blocked compression-induced spinal NK1r internalization. After 5 days of morphine infusion, thermal escape latencies were the same as in preinfusion animals or saline-infused controls, and compression-evoked NK1r internalization was no longer suppressed. Systemic administration of naloxone to rats on day 6 of morphine infusion resulted in prominent withdrawal behaviors and a concomitant increase in NK1r internalization in dorsal horn. The naloxone-induced internalization was blocked by NK1r antagonist L-703,606 [cis-2-(diphenylmethyl)-N-[(2-iodophenyl)methyl]-1 azabicyclo[2.2.2]octan-3-amine] or pretreatment with capsaicin, confirming that the internalization is due to the endogenous SP release from the primary afferents. We conclude that inability to suppress release of excitatory neurotransmitters/neuromodulators from primary afferents by morphine after chronic exposure is an important component in spinal morphine tolerance, and excessive release from these afferents contributes to the spinal morphine withdrawal syndrome.

Managing acute postoperative pain: Is 3 hours too long?

This case study discusses a 64-year-old opioid-tolerant patient who underwent amputation below the left knee and received pain management in the PACU. The patient's self-reported pain level remained 9 on a 0 to 10 scale despite having received a total of 62 mg of morphine sulfate (MSO 4 ) and 60 mg of ketorolac in just less than 3 hours. The patient's facial expression corresponded to a score of 4 to 5 based on the Wong-Baker Faces Pain Scale. This case study illustrates that it is crucial to promptly involve the pain management service when an opioid-tolerant patient requires aggressive pain treatment. The initial patient-controlled analgesia (PCA) order and MSO 4 -loading doses must take into account the patient history of opioid tolerance, increasing the frequency and dosage-loading doses of MSO 4 for treating severe pain until the patient's pain is reduced by at least 50% on a numeric scale, or until the patient states satisfactory relief. The most important rule of pain management is that pain is what the patient says it is.

Epidural analgesia for acute symphysis pubis dysfunction in the second trimester

We report a case of severe symphysis pubis dysfunction in a parturient during her second trimester of a twin pregnancy. Symphysis pubis dysfunction produces pain, instability and limitation of mobility and function, of the symphysis pubis during pregnancy and labour. It is often under-treated. We provided lumbar epidural analgesia with intermittent top-ups of bupivacaine 0.1% with fentanyl 2μg/mL for 72h. This provided initial analgesia, breaking a vicious cycle of pain and muscle spasm. The benefits extended into the remainder of her pregnancy. Subsequently, simple analgesics and physiotherapy allowed control of pain until vaginal delivery 15 weeks later.

Effect of VMH lesion on sucrose-Fed nociceptive responses.

An initial analgesia followed by hyperalgesia to phasic noxious stimuli occurs after ingestion of sucrose ad libitum. However, the mechanism underlying hyperalgesia is not known. The present study was designed to explore the role of VMH in the mediation of the hyperalgesic effect of sucrose ingestion. Adult male albino rats received sucrose solution (20% p.o.) in addition to laboratory food pellets and tap water ad libitum. Their behavioural responses to various phasic and tonic noxious stimuli were recorded after 6, 12 and 48 h during pre and post-sucrose fed states in both the control and VMH lesion groups of rats. Sucrose feeding to control rats significantly reduced the tail flick latency (TFL) and threshold of vocalization during stimulus (SV) and after discharge (VA) indicating hyperalgesia, while the threshold of tail flick remained unaffected. The average pain rating during the formalin test (tonic pain) decreased significantly indicating analgesia. VMH lesion decreased the latency (mean +/- SD) for tail flick (11.26 +/- 4.65 from 15.61 +/- 5.12 s), threshold (median) for tail flick (0.04 from 0.08 mA), vocalization during stimulus (0.05 from 0.1 mA) and vocalization after discharge (0.15 from 0.2 mA), while the tonic pain rating increased, thereby suggesting a hyperalgesic state. However, sucrose feeding to lesioned rats neither potentiated nor attenuated their hyperalgesia. The results suggest that sucrose feeding for 6-48 h ad libitum produces hyperalgesia to phasic noxious and analgesia to tonic noxious stimuli, while VMH lesion produces hyperalgesia to both phasic and tonic noxious stimuli. Secondly, sucrose ingestion by VMH lesion rats does not affect their responses to pain, suggesting the possible role of VMH in the mediation of sucrose-fed nociceptive responses.

Comparison of low-dose epidural with combined spinal-epidural analgesia for labour

We have performed a randomized comparison of two low-dose epidural regimens for analgesia in labour, differing only in the manner in which initial analgesia was established. In the epidural (EPI) group, 484 women received a loading dose of 20 ml of 0.1% bupivacaine with fentanyl 2 micrograms ml-1. In the combined spinal-epidural (CSE) group, 524 women received a spinal injection of plain bupivacaine 2.5 mg with fentanyl 25 micrograms. In both groups, these initial doses were followed by 0.1% bupivacaine with fentanyl 2 micrograms ml-1 infused at a rate of 12 ml h-1, with 20-ml top-ups for breakthrough pain. The groups were compared for midwife assessment of analgesic efficacy, delivery mode, patient assessments of first stage analgesia, second stage analgesia, overall analgesia, motor block and complications. Midwives, who were not blinded to the treatment groups, assessed 61.6% of CSE as providing 'excellent' analgesia compared with 56.4% of epidurals (P = 0.02). Patients assessed overall analgesia as 'excellent' in 74.8% of CSE compared with 71.7% of epidurals (P = 0.14). Other comparisons between groups revealed no differences. These findings may have been affected by an uneven distribution of multiparous women between the groups (25% in the EPI group and 34.2% in the CSE group; P = 0.002). However, subgroup analysis of primiparous and multiparous women did not alter the results.

Efficacy and complications of morphine infusions in postoperative paediatric patients.

The aim of the study was to evaluate the efficacy and the incidence of clinically significant adverse drug reactions (ADRs) in paediatric patients receiving continuous intravenous morphine infusions for acute postoperative pain. Definitions were established for ADRs and data were collected in an immediately retrospective fashion for a maximum of 72 h in 110 patients >/=5 three months of age (0.3-16.7 years) receiving morphine infusions and admitted to a general ward over a three month convenience sampling period. Inadequate analgesia occurred in 65.5% of patients during the first 24 h of therapy and occurred most frequently in patients with infusion rates of 20 microg.kg-1.h-1 or less. Nausea/vomiting was the most commonly experienced ADR (42.5%). The incidence of respiratory depression was 0% (95% CI=0-3.3%). Other ADRs included: urinary retention (13.5%), pruritus (12.7%), dysphoria (7.3%), hypoxaemia (4.5%), discontinuation of morphine for treatment of an ADR (3.6%), and difficulty in arousal (0.9%). The most common ADRs associated with morphine infusions were inadequate analgesia (in the first 24 h) and nausea/vomiting. There were no cases of respiratory depression. Methods of avoiding initial inadequate analgesia and treating nausea and vomiting associated with morphine infusions are needed.

Epidural Ropivacaine Infusion for Postoperative Analgesia After Major Lower Abdominal Surgery--A Dose Finding Study

Ropivacaine exhibits less cardiotoxicity and causes less motor block than bupivacaine when used in equianalgesic doses.This makes ropivacaine potentially well suited for epidural infusion for postoperative analgesia. The aim of this study was to determine which of three concentrations of epidurally administered ropivacaine infused for postoperative analgesia would attenuate intravenous opioid analgesia requirements while also minimizing motor block. Forty ASA I-III patients, having major lower abdominal surgery, completed the study. They were randomly assigned to one of four treatment groups: Group S, control, epidural saline (n = 10); Group 1, epidural 0.1% ropivacaine (n = 10); Group 2, epidural 0.2% ropivacaine (n = 10); and Group 3, epidural 0.3% ropivacaine (n = 10). The study was double-blind. Initial epidural analgesia was established with 0.5% ropivacaine, and then general anesthesia induced for surgery. Once in the recovery room, epidural infusions were commenced at 10 mL/h and maintained at that rate for 21 h. Intravenous patient controlled analgesia (PCA) morphine was used as required by the patients for supplemental analgesia. Total PCA morphine use was more over the 21-h period in Group S than all the ropivacaine groups, being significantly so for Group 2 (median values: Group S, 43.3 mg; Group 1, 18.7 mg; Group 2, 7.5 mg; Group 3, 19 mg; for Group 2, P = 0.03). Visual analog scale (VAS) scores on coughing were significantly lower (i.e., less pain) than control for all ropivacaine groups after 4 h of infusion and also for Groups 2 and 3 after 8 h of infusion. (Median VAS (mm) on coughing at 8 h: Group S = 70, Group 1 = 56, Group 2 = 32, Group 3 = 0; for Groups 2 and 3, P < 0.05 compared to Group S). There was a dose-related increase in the amount of motor block, with Group 3 having significantly more motor block than all other groups at 4 and 8 h. For postoperative analgesia, the epidural infusion of 0.2% ropivacaine provided the best balance of analgesia with minimal motor block. (Anesth Analg 1995;81:982-6)

Transdermal fentanyl in combination with initial intravenous dose titration by patient-controlled analgesia

Two studies including a total of 70 patients evaluated the efficacy and side effects of a combination of initial patient-controlled analgesia (PCA) for dose finding with transdermal fentanyl administration. Patients, requiring strong opioids for severe cancer pain, received intravenous (i.v.) fentanyl on an on-demand basis over a 24 h period. The amount of fentanyl administered was then used for selecting a suitable transdermal therapeutic system (TTS), which remained in place for 72 h. The size of the second TTS was adjusted according to the amount of supplementary i.v. fentanyl required on day 3. Beginning on day 4, oral or subcutaneous morphine was made available as a rescue medication. The use of TTS fentanyl in combination with initial dose titration using PCA resulted in rapid and statistically significant pain relief in both studies. A respiratory rate below 8 per minute was observed in three patients. Due to adequate symptomatic treatment, other moderate and severe symptoms were relatively rare. TTS fentanyl was shown to be an effective, safe and simple method for long-term pain relief in cancer patients and presents an interesting novel option in the treatment of cancer pain.

Double-blind comparison of intravenous butorphanol (Stadol) and fentanyl (Sublimaze) for analgesia during labor

Objective: Our purpose was to compare the analgesic properties, effect on labor, and maternal-fetal side effects of intravenous butorphanol and fentanyl.Study Design: One hundred patients with uncomplicated term pregnancies were enrolled during early active labor. Each patient received standard doses of either fentanyl (50 to 100 μg) or butorphanol (1 to 2 mg) hourly on request in a double-blind manner. Pain was scored independently by the nurse and patient with a 10-point visual analog scale. Categoric and measurement data were collected for comparison of the effects on uterine activity, maternal and fetal well-being, and neonatal outcomes.Results: The fentanyl (n = 50) and butorphanol (n = 50) groups were identical with respect to maternal age, race, parity, and weight. Greater improvement in pain relief was found after the first dose of butorphanol than after fentanyl (p < 0.05). When fentanyl was given, either more doses were necessary (3.2 ± 1.3 vs 2.1 ± 1.1, p < 0.01) or epidural analgesia was requested more often (16%, 32% vs 9%, 18%, p < 0.05). Uterine contraction patterns for the first hour after dosing were unchanged, and the duration of the first and second stages of labor were not different between the two groups. No differences in maternal or newborn adverse effects were observed.Conclusions: Both drugs were equally safe and without effect on active labor. Butorphanol provided better initial analgesia than fentanyl with fewer patient requests for more medication or epidural analgesia.

Cholecystokinin receptor binding in morphine analgesia: Tolerance, withdrawal and abstinence

The effect of morphine treatment on cholecystokinin (CCK) receptor binding in rat cerebral cortex was investigated. Subcutaneous implantation and removal of Alzet miniosmotic pumps, releasing morphine, permitted us to establish the phases of initial analgesia, tolerance to the analgesic action of morphine, morphine withdrawal and abstinence. CCK receptor binding in rat cerebral cortex never differed from the values obtained from animals implanted with saline-releasing minipumps. The results of the present study suggest that the putative changes in the interaction between opioidergic and CCKergic neurotransmission at different stages of morphine treatment and withdrawal are not caused by changes of CCK receptor binding properties.

Transdermal Fentanyl and Initial Dose-Finding with Patient-Controlled Analgesia in Cancer Pain. A Pilot Study with 20 Terminally Ill Cancer Patients

This pilot study evaluated the efficacy and side effects of a combination of initial patient-controlled analgesia (PCA) for dose-finding with transdermal fentanyl administration. Twenty inpatients, requiring strong opioids for severe cancer pain, received intravenous fentanyl on an on-demand basis over a 24-h period. The amount of fentanyl administered was then used as a guideline for selecting a suitable transdermal therapeutic system (TTS) on the 2nd day, which remained in place for 3 days. The size of a 2nd TTS, being used from day 5 to 7, was adjusted according to the amount of supplementary intravenous fentanyl doses on day 3. From day 4 to 7 intravenous fentanyl was stopped, and subcutaneous morphine was made available as a rescue medication. A standardized adjuvant medication was allowed. Pain intensity, pain relief, quality of sleep, mood, general state of health, activity, mobility, rescue morphine consumption and side effects were assessed using a diary after baseline pain and symptoms were recorded. Vital functions were monitored and fentanyl plasma levels were measured daily in 15 patients. The use of TTS fentanyl in combination with initial dose titration using PCA gave rapid and statistically significant pain relief. Patient compliance and acceptance were excellent. In the absence of severe side effects the main complaints were dryness of the mouth and constipation. Increasing pain intensity and increasing supplementary morphine requirements as well as decreasing plasma fentanyl levels on day 7 may indicate that conversion ratios from intravenous to transdermal administration should be increased or that TTS should be changed earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and experimental effects of informational stress

Under certain conditions, information may become stressful. In the initial stages of our research we found that informational stress can result in fatigue, anxiety, sleeplessness, and excitability. Later we found further symptoms, such as tachycardia, palpitations, chest pain, abdominal pain, increase or decrease of appetite, diarrhoea or constipation, muscle cramps, back pain, headache, tremor, dizziness, diaphoresis, tics, and so on. Some of these symptoms might be the result of cathecholamine increased secretion, others of a decrease of endogenous opioids. Because in the initial stage of stress analgesia may occur, we studied the clinical and experimental evolution of the pain threshold and its clinical manifestations. We found that after the initial analgesia, there follows a stage of hyperalgesia; the symptoms of this stage very much resemble those of the opioid abstinence syndrome. The evolution of this syndrome is enhanced by naloxone, an opioid antagonist, and it is attenuated by clonidine and propranolol, used in the treatment of opioid abstinence syndrome. Thus we demonstrated that in the latter stage of stress, there is diminished secretion of endogenous opioids and an acute tolerance to them.

Transdermal fentanyl and initial dose-finding with patient-controlled analgesia in cancer pain. A pilot study with 20 terminally ill cancer patients

This pilot study evaluated the efficacy and side effects of a combination of initial patient-controlled analgesia (PCA) for dose-finding with transdermal fentanyl administration. Twenty inpatients, requiring strong opioids for severe cancer pain, received intravenous fentanyl on an on-demand basis over a 24-h period. The amount of fentanyl administered was then used as a guideline for selecting a suitable transdermal therapeutic system (TTS) on the 2nd day, which remained in place for 3 days. The size of 2nd TTS, being used from day 5 to 7, was adjusted according to the amount of supplementary intravenous fentanyl doses on day 3. From day 4 to 7 intravenous fentanyl was stopped, and subcutaneous morphine was made available as a rescue medication. A standardized adjuvant medication was allowed. Pain intensity, pain relief, quality of sleep, mood, general state of health, activity, mobility, rescue morphine consumption and side effects were assessed using a diary after baseline pain and symptoms were recorded. Vital functions were monitored and fentanyl plasma levels were measured daily in 15 patients. The use of TTS fentanyl in combination with initial dose titration using PCA gave rapid and statistically significant pain relief. Patient compliance and acceptance were excellent. In the absence of severe side effects the main complaints were dryness of the mouth and constipation. Increasing pain intensity and increasing supplementary morphine requirements as well as decreasing plasma fentanyl levels on day 7 may indicate that conversion ratios from intravenous to transdermal administration should be increased or that TTS should be changed earlier. Special indications for this combination may be in patients with dysphagia or vomiting, where pain management could be facilitated.

Clinical use of sufentanill as an anesthetic

This review considers a few of the controversies and most recent data pertaining to the clinical intraoperative use of the potent opioid sufentanil. Although sufentanil is used extensively as the opioid component of “balanced” anesthesia, opioids themselves are not total anesthetics. Sufentanil is effective in reducing the so-called stress responses that can occur with balanced anesthesia. Although no conclusive data have shown that such reduction in stress response improves anesthetic outcome, many clinicians continue to choose sufentanil for both convenience and improved hemodynamic control. Recent pharmacokinetic modeling suggests that sufentanil would be a good choice for balanced anesthesia. Additionally, initial postoperative analgesia appears to work better when sufentanil rather than fentanyl is used intraoperatively. Although cost considerations remain important, cost analysis would suggest that, on a per-patient basis, choice of intraoperative opioid has very little effect on total hospital costs.

ANALGESIA FOR LABOUR AND DELIVERY USING INCREMENTAL DIAMORPHINE AND BUPIVACAINE VIA A 32–GAUGE INTRATHECAL CATHETER

Twenty mothers who had requested regional analgesia during labour had a 32-gauge catheter inserted into the lumbar subarachnoid space. The mean time to place the catheters was 116 s (range 55-270 s) and there were no technical difficulties. Incremental diamorphine was given, up to a maximum initial dose of 0.5 mg. Analgesia was excellent in 11 mothers, good in seven and unsatisfactory in two. The duration of initial analgesia from diamorphine was 101 min (range 30-170 min). Eight mothers were able to move about during the first stage, with effective analgesia. Side effects were common: 15 mothers had pruritus, 15 had nausea or vomiting, and eight had mild sedation. No mother had a ventilatory frequency of less than 12 b.p.m. in the 12 h after the last dose of intrathecal diamorphine. Intrathecal 0.5% bupivacaine was given to 16 mothers in the first stage because the analgesia after a top-up with diamorphine became insufficient later in the labour. Fifteen mothers were pain free after bupivacaine; there was one failure. The initial effective dose of bupivacaine was between 0.25 ml and 2 ml. The maximum height of the block after bupivacaine was T9, and there was no hypotension. Nine mothers were given hyperbaric 0.5% bupivacaine 1-2 ml during the second stage; all were pain free for the procedure. The maximum force needed to withdraw the catheters was 700 g; and all catheters were removed intact. There were no post-spinal headaches.

Do the pharmacodynamics of the nonsteroidal anti-inflammatory drugs suggest a role in the management of postoperative pain?

Until recently, nonsteroidal anti-inflammatory drugs (NSAIDs) were regarded as weak analgesic agents with a potent antiplatelet effect that severely limited their perioperative usefulness. However, the recent development of injectable NSAIDs has stimulated a re-evaluation of the potential role of this class of drugs in postoperative pain management. In general surgery, NSAIDs have been shown to be effective analgesics when administered after surgery, as judged by either a reduction in pain scores and/or by an opioid sparing effect. Parenteral NSAIDs alone, notably ketorolac and diclofenac, may be adequate or even preferred analgesic agents after minor surgery. In dental surgery, NSAIDs produce greater initial analgesia than steroids, although the latter produce greater suppression of swelling and less functional loss. NSAID pretreatment results in only modest suppression of swelling compared with placebo. These data suggest that the acute analgesic effects of NSAIDs in oral surgery and probably other models result from suppression of a nociceptive process, rather than a generalised anti-inflammatory effect. This view challenges the traditional association between inhibition of prostaglandin synthesis and the therapeutic effects of these drugs. The variety of NSAIDs leads to a range in half-lives from short, e.g. diclofenac (1 h), intermediate, e.g. ketorolac (5h), to long, e.g. tenoxicam (60h), which has implications for both convenience of the dosage regimen and drug accumulation. For some racemic NSAIDs (e.g. ibuprofen), metabolic 'activation' of the inactive R-enantiomer to the active S-enantiomer occurs. Renal dysfunction may increase both the plasma concentration and body residence time of NSAIDs, thereby increasing the risk of adverse effects. The concomitant effects of anaesthesia have not yet been studied. The principal concern regarding the use of perioperative NSAIDs is the risk of decreased haemostasis and wound healing. Although it has been found that NSAIDs prolong bleeding times in patients, values generally remain below the upper limits of those in generally healthy patients. Healing of gastrointestinal anastomoses may be compromised by NSAID administration but corneal healing and bone remodelling are not. There is a need for further research into the potential for renal side effects with NSAIDs in the perioperative setting, where the effects of anaesthesia and surgery may increase the risk of side effects, particularly in elderly patients. The main benefits of NSAIDs derive from opioid sparing (e.g. reduction in perioperative nausea and vomiting and improvement in ventilation), although some studies allude to an enhanced quality of analgesia from the combination compared with either NSAID or opioid alone. The question of pre- vs postinjury treatment with NSAIDs remains unresolved.

Conditioned and unconditioned stress-induced analgesia: Stimulus preexposure and stimulus change

Aversive events such as electric shock lead to analgesia. There have been differing views with regard to whether the aversive event itself can lead to analgesia as a direct unconditioned reaction, or whether the analgesia is instead a reaction to fear conditioned to cues present during shock or to other associative processes initiated by the aversive event. Maier (1989, 1990) has argued that aversive events such as shock lead to both types of analgesia, with the type observed depending on test conditions. Unconditioned analgesia was argued to be present soon after shock, with conditioned analgesia replacing the unconditioned form if the subject is allowed to remain in the shock environment. Consistent with this argument, the experiments reported here show that (1) preexposure to the environment in which shock later occurs has no effect on the analgesia soon after shock, but eliminates the later analgesia; (2) the initial postshock analgesia is unaffected by removing the subject from the shock environment to a different environment, but the later reaction is prevented by such a change; (3) returning the subject to the shock environment after confinement in a nonshock environment rearouses an analgesic reaction; and (4) this rearousal does not occur if the subject has first been confined to the shock environment without shock.