Association of peri-operative prescription of non-steroidal anti-inflammatory drugs with continued prescription of opioids after total knee arthroplasty: a retrospective claims-based cohort study.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the mainstays of multimodal pain management. While effective for acute pain control, recent pre-clinical evidence has raised concerns regarding an association between NSAIDs and chronic pain and potential opioid use. Our objective was to explore the association between peri-operative use of prescription NSAIDs and the need for continued opioid prescriptions lasting 90-180 days in previously opioid-naïve patients undergoing total knee arthroplasty. A database of health claims in the USA was used to identify all opioid-naïve adult patients who underwent primary knee arthroplasty between January 2010 and October 2021. We evaluated the magnitude of association between peri-operative prescription NSAID claims and claims for opioids at 90 days postoperatively using multivariable logistic regression models. Secondary outcomes included: the magnitude of association between peri-operative NSAID prescription and claims for opioids at 180 days postoperatively; and identifying other potential factors associated with opioid claims at 90 days postoperatively. After risk adjustment using multivariable logistic regression models in the 789,736-patient cohort, the adjusted odds ratio (95%CI) for a continuous claim of opioids at 90 and 180 days postoperatively among patients with a peri-operative NSAID prescription within 30 days was 1.32 (1.30-1.35), p < 0.001; and 1.12 (1.10-1.15), p < 0.001, respectively. This estimate of effect remained robust at 90 days after accounting for known potential confounders, including pre-existing knee pain and acute postoperative pain severity. Similar analysis of other pain medications (e.g. paracetamol) did not detect such an association. This population-based cohort study suggests that peri-operative prescription NSAID use may be associated with continued opioid prescription claims at 90 and 180 days after knee arthroplasty, even after adjusting for other observed covariates for continuous opioid claims. These novel findings can inform clinical decision-making for post-surgical pain management, risk-benefit discussions with patients and future research.

Adverse event assessment and reporting in trials of newer treatments for post-operative pain.

BACKGROUND: Assessment and reporting of adverse events (AEs) in studies of perioperative interventions is critical given the potential for unintended and preventable iatrogenic morbidity and mortality. This focused review evaluated the quality of AE assessment and reporting in acute post-operative pain treatment trials. Since older analgesics (e.g., opioids, NSAIDs) already have a well-characterized safety profile, we concentrated on trials of pregabalin and gabapentin as a representative sample of studies where the perioperative safety profile was relatively unknown. METHODS: We reviewed primary reports of trials of pregabalin and gabapentin for treatment of acute post-operative pain for: (1) adherence to the 10 recommendations from the 'CONSORT Extension for Harms,' (2) AE assessment method, (3) timing of AE assessment and reporting, and (4) assessment and reporting of AE severity. RESULTS: We identified 31 trials of pregabalin and 59 of gabapentin. The median number of CONSORT harms recommendations that were satisfied was 7 of 10. The most common (41%) method of AE assessment was direct questioning about specific AEs by investigators. However, AE assessment method was not described in 18% of trials. AE assessments were reported for specified perioperative time points in only 24% of trials. Of greatest concern, no AE data were reported whatsoever in 8 of the included publications. CONCLUSIONS: Considerable widespread improvements are needed in AE reporting for post-operative pain treatment trials. In addition to heightened awareness among clinical investigators, mandatory journal editorial policies may further facilitate improvements in safety assessment and reporting.

Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society.

Neuropathic pain (NeP), generated by disorders of the peripheral and central nervous system, can be particularly severe and disabling. Prevalence estimates indicate that 2% to 3% of the population in the developed world suffer from NeP, which suggests that up to one million Canadians have this disabling condition. Evidence-based guidelines for the pharmacological management of NeP are therefore urgently needed. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment are based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Analgesic agents recommended for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Recommended fourth-line treatments include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy, such as lamotrigine, topiramate and valproic acid. Treatment must be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Further studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes, and treatment of pediatric and central NeP.

The effects of intrathecal gabapentin on spinal morphine tolerance in the rat tail-flick and paw pressure tests.

Analgesic tolerance to opioids has been described in both experimental and clinical conditions and may limit the clinical utility of these drugs. We have previously shown that systemic gabapentin (GBP), a non-opioid drug, prevents and reverses tolerance to systemic morphine in the rat. In this study, we investigated the effect of intrathecal GBP on spinal morphine tolerance. Studied rats were given 7 days of intrathecal injections with saline (10 microL), GBP (300 microg), morphine (15 microg), or a GBP-morphine combination, and analgesic testing using tail-flick and paw-pressure tests was conducted before and 30 min after the drug injection. On Day 8, an antinociceptive dose-response curve was constructed and the 50% effective dose (ED(50)) values for morphine (given alone) were calculated for each study group. Coinjection of GBP with morphine blocked the development of tolerance, as shown by the preservation of morphine analgesia over 7 days as well as by a concomitant decrease in ED(50) values on Day 8, as compared with the morphine-alone group. Although additive analgesia over Days 1-7 cannot be ruled out, ED(50) reductions in the GBP-morphine combination group indeed suggest some suppression of tolerance. These data support previous evidence that GBP prevents opioid tolerance and, more specifically, indicate that intrathecal GBP prevents the development of spinal opioid tolerance. Future studies are required to examine the respective roles of supraspinal and peripheral sites of GBP-morphine interaction and to investigate the mechanisms underlying the action of GBP on opioid tolerance.

LY-293558. Eli Lilly & Co.

Lilly is developing the racemic compound LY-215490, a selective and competitive AMPA antagonist, as a potential treatment for cerebral infarction, cerebrovascular ischemia, epilepsy and as an analgesic [135089], [158980], [254029], [278691]. By January 2000, LY-293558 was undergoing phase II trials for pain [414000].

Hemispheric lateralization of somatosensory processing.

Processing of both painful and nonpainful somatosensory information is generally thought to be subserved by brain regions predominantly contralateral to the stimulated body region. However, lesions to right, but not left, posterior parietal cortex have been reported to produce a unilateral tactile neglect syndrome, suggesting that components of somatosensory information are preferentially processed in the right half of the brain. To better characterize right hemispheric lateralization of somatosensory processing, H(2)(15)O positron emission tomography (PET) of cerebral blood flow was used to map brain activation produced by contact thermal stimulation of both the left and right arms of right-handed subjects. To allow direct assessment of the lateralization of activation, left- and right-sided stimuli were delivered during separate PET scans. Both innocuous (35 degrees C) and painful (49 degrees C) stimuli were employed to determine whether lateralized processing occurred in a manner related to perceived pain intensity. Subjects were also scanned during a nonstimulated rest condition to characterize activation that was not related to perceived pain intensity. Pain intensity-dependent and -independent changes in activation were identified in separate multiple regression analyses. Regardless of the side of stimulation, pain intensity--dependent activation was localized to contralateral regions of the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, and bilateral regions of the cerebellum, putamen, thalamus, anterior cingulate cortex, and frontal operculum. No hemispheric lateralization of pain intensity-dependent processing was detected. In sharp contrast, portions of the thalamus, inferior parietal cortex (BA 40), dorsolateral prefrontal cortex (BA 9/46), and dorsal frontal cortex (BA 6) exhibited right lateralized activation during both innocuous and painful stimulation, regardless of the side of stimulation. Thus components of information arising from the body surface are processed, in part, by right lateralized systems analogous to those that process auditory and visual spatial information arising from extrapersonal space. Such right lateralized processing can account for the left somatosensory neglect arising from injury to brain regions within the right cerebral hemisphere.

Topiramate in trigeminal neuralgia: a randomized, placebo-controlled multiple crossover pilot study.

We conducted a pilot study to evaluate the efficacy of topiramate in trigeminal neuralgia using a randomized, double-blind, placebo-controlled, two-period crossover design. Three patients were enrolled in and completed the study. All three patients responded to topiramate in this main study and entered a subsequent confirmatory study consisting of three topiramate-placebo crossovers. In the main study, topiramate reduced pain by 31%, 42%, and 64% in the three patients (p = 0.04). However, topiramate showed no effect in the confirmatory study. Given that trials of less common pain conditions are fraught with low patient recruitment rates, a multiple crossover design provides more information, which is important in conditions associated with considerable pain fluctuation. Larger trials are needed to more precisely estimate the effect of topiramate in trigeminal neuralgia.

A randomized, controlled trial of high-dose dextromethorphan in facial neuralgias.

BACKGROUND: NMDA glutamate receptor antagonists such as ketamine and dextromethorphan reduce pain in certain neuropathic pain conditions. However, there have been no controlled trials of NMDA antagonists in facial neuralgias. METHODS: A randomized, double-blind, crossover trial compared 6 weeks of oral dextromethorphan with active placebo (low-dose lorazepam) in 19 patients, stratified into three groups: 11 with facial pain and possible trigeminal neuropathy, five with anesthesia dolorosa, and three with idiopathic trigeminal neuralgia. Dosage was titrated in each patient to the highest level reached without disrupting normal activities. RESULTS: Patients completing the trial included 10 with possible trigeminal neuropathy, four with anesthesia dolorosa, and two with trigeminal neuralgia. In patients with possible trigeminal neuropathy and anesthesia dolorosa, dextromethorphan decreased pain by a mean of only 2 to 4%, and these estimates were not significant. Both patients with trigeminal neuralgia had more pain during dextromethorphan treatment than during placebo treatment. Of three patients who demonstrated an analgesic response to dextromethorphan during the main trial, only one repeatedly responded in four subsequent confirmatory drug-placebo crossovers. CONCLUSIONS: Dextromethorphan shows little or no analgesic efficacy in pain due to possible trigeminal neuropathy and anesthesia dolorosa. Additional trials are necessary to conclusively evaluate the efficacy of NMDA-receptor antagonists in trigeminal neuralgia.

Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain.

BACKGROUND: Previous studies suggest that 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA)/kainate antagonists reduce experimentally induced pain. There have been no studies of AMPA/kainate antagonists in clinical pain. METHODS: Analgesic efficacy of intravenous LY293558 (0.4 or 1.2 mg/kg) was compared with that of intravenous ketorolac tromethamine (INN, ketorolac; 30 mg) and placebo in a randomized, double-blind, parallel-group study after oral surgery (n = 70). Study drugs were administered at the onset of moderate pain; pain intensity and relief were measured for 240 minutes. RESULTS: High-dose LY293558 and ketorolac tromethamine were superior to placebo (P < .05) for pain evoked by mouth opening and one of several measures of spontaneous pain: SPID240 +/- SEM for pain evoked by mouth opening was highest for ketorolac tromethamine (151 +/- 58), intermediate for high-dose LY293558 (-45 +/- 35), and least for low-dose LY293558 (-151 +/- 39) and placebo (-162 +/- 50). High-dose LY293558 was superior to placebo at individual time points (45 to 240 minutes) for pain evoked by mouth opening but not for spontaneous pain. The spontaneous summed pain intensity difference over 240 minutes (SPID240 +/- SEM) was highest for ketorolac tromethamine (303 +/- 84), intermediate for high-dose LY293558 (-51 +/- 40) and low-dose LY293558 (-96 +/- 45), and least for placebo (-180 +/- 24). LY293558 was well tolerated, with dose-dependent and reversible side effects including hazy vision in 20% of patients and sedation in 15%. CONCLUSIONS: This is the first evidence that an AMPA/kainate antagonist reduces clinical pain. Tests of evoked pain may be more sensitive to certain analgesics than those of spontaneous pain. The evaluation of evoked pain as an outcome measure in analgesic trials may identify potentially useful compounds otherwise missed if only spontaneous pain is evaluated.

Pre- versus postformalin effects of ketamine or large-dose alfentanil in the rat: discordance between pain behavior and spinal Fos-like immunoreactivity.

UNLABELLED: The purpose of this animal investigation was to compare behavioral responses with spinal Fos-like immunoreactivity (FLI) after pre-versus postformalin administration of anesthetic doses of IV ketamine or alfentanil. Preformalin and postformalin injection (1.5% subcutaneously) treatment groups included IV saline control (1.5 mL/kg), ketamine (10 mg/kg), and alfentanil (170 microg/kg). In the behavioral study group, nociceptive behavior was evaluated 15-60 min after hindpaw formalin injection. In the spinal FLI study group, rats were perfused 2 h postformalin, and spinal cords were dissected, sliced at 30 microm, and processed by immunoperoxidase staining with an antibody against the Fos protein. Quantification and determination of the laminar distribution of Fos-labeled nuclei were performed at the L4-5 spinal level ipsilateral to formalin injection. Ketamine produced a selective preemptive analgesic effect in behavioral formalin experiments, yet failed to suppress spinal FLI. In contrast, alfentanil failed to demonstrate a selective preemptive analgesia in behavioral experiments, but did produce preemptive suppression of spinal FLI. Together with previous data from our laboratory, we conclude that behavioral analgesia and spinal Fos expression may be uncoupled under certain circumstances. IMPLICATIONS: In this study, we compared pain reduction produced by IV drugs (ketamine or alfentanil) with the ability to prevent injury-induced spinal cord changes. We measured pain behavior and spinal Fos protein after rats received ketamine or alfentanil before versus after formalin injection. Fos inhibition patterns did not clearly correlate with pain reduction, providing further evidence that Fos inhibition is not always predictive of behavioral analgesia.

Pre- versus postinjury effects of intravenous GABAergic anesthetics on formalin-induced Fos immunoreactivity in the rat spinal cord.

UNLABELLED: We evaluated the suppression of spinal Fos-like immunoreactivity (FLI) by i.v. anesthetics in the rat formalin model. Preformalin injection (1.5% subcutaneously) treatment groups included i.v. saline controls and three i.v. GABAergic anesthetic groups (pentobarbital 20 mg/kg, propofol 10 mg/kg, or alphaxalone 1.5 mg/kg; n = 12 per group). After perfusion 2 h postformalin, spinal cords were dissected, sliced at 30 microm, and processed by immunoperoxidase staining with an antibody against the Fos protein. Quantification and determination of the laminar distribution of Fos-labeled nuclei were performed at the L4-5 spinal level ipsilateral to formalin injection. Drug groups demonstrating FLI suppression were comparatively studied in a 5-min postformalin treatment group. Pentobarbital pretreatment failed to suppress FLI. However, significant reductions (percent decrease) of FLI were observed with propofol (63%) and alphaxalone (30%) compared with saline controls. Pre- versus postformalin comparison studies showed that propofol, but not alphaxalone, suppressed FLI more effectively when given preformalin. Given the observed inconsistencies between this study of Fos expression and our previous behavioral study, it is questionable whether anesthetic modulation of noxious stimulus-induced FLI parallels that of behavioral responses. IMPLICATIONS: In this study, we examined whether i.v. general anesthetics (propofol, alphaxalone, and pentobarbital) prevent injury-induced spinal cord changes. We measured spinal Fos protein after rats received anesthetics before versus after a formalin injection. Fos inhibition patterns were inconsistent with behavioral studies of these anesthetics, suggesting that Fos inhibition does not always correlate with behavioral analgesia.

40 Hz auditory steady-state response and EEG spectral edge frequency during sufentanil anaesthesia.

PURPOSE: The auditory steady-state evoked response (ASSR) is an evoked potential which provides a sensitive measure of the effects of general anaesthetics on the brain. We used pharmacokinetic-pharmacodynamic (PK-PD) modelling to compare the effects of sufentanil on the amplitude of the ASSR with its effect on spectral edge frequency (SEF) of the electroencephalogram. METHODS: Nine patients scheduled for elective cardiac surgery participated. Midazolam (70 micrograms.kg-1 i.m.) was given 60 min before entering the operating room. Anaesthesia was induced with 5 micrograms.kg-1 sufentanil at a rate of 0.83 microgram.kg-1.min-1. The ASSR, SEF and plasma sufentanil concentrations were measured for 30 min after induction of anaesthesia before surgery. The half-life between the central and effect site compartments (t1/2Keo), the 50% inhibitory concentration (IC50) and the slope factor (gamma) were computed. RESULTS: The amplitude of the ASSR increased during the first three minutes of infusion of sufentanil by up to 40%. This was followed by a rapid decrease between the fourth and fifth minutes to 16% of baseline. The SEF decreased progressively during the first five minutes of infusion to 18% of baseline. Both measures subsequently showed modest recovery. The parameters gamma, IC50 and t1/2Keo for ASSR were (mean +/- SD) 6.0 +/- 3.7, 2.1 +/- 1.2 ng.ml-1 and 7.3 +/- 2.4 min. For SEF the values were 5.9 +/- 5.2, 1.4 +/- 0.7 ng.ml-1 (P < 0.05 compared with ASSR) and 6.8 +/- 2.4 min. CONCLUSION: The sensitivity of ASSR to sufentanil is less than that of the SEF.

Protamine-induced hypotension and bradycardia in a cardiac transplant patient.

PURPOSE: The potential for functional reinnervation of the transplanted heart in man is controversial. We report the sudden onset of bradycardia in a cardiac transplant patient following a period of hypotension subsequent to the administration of protamine. Possible mechanisms underlying this response, including reinnervation of the transplanted heart, are assessed. CLINICAL FEATURES: Eight weeks after cardiac transplantation, a patient returned to hospital for a left femoral-tibial artery bypass vein graft. The patient was anaesthetized using general anaesthesia. Upon completion of the procedure, protamine was administered to reverse the heparin-induced anticoagulation. Although administration of a 5.0 mg "test-dose" appeared to be without cardiovascular effect, after an additional 20.0 mg, blood pressure decreased from 98/52 to 62/40 mmHg. After blood pressure reached its nadir, heart rate decreased precipitously from 57 to 29 beats.min-1. CONCLUSIONS: This report demonstrates that heart rate can change considerably in patients who have undergone cardiac transplantation. It is argued that the change in heart rate observed in the present report cannot be explained by reinnervation of the transplanted heart, as the patient had undergone transplantation only eight weeks previously. Rather, we suggest that the change was mediated by mechanisms intrinsic to the transplanted heart and extrinsic to the CNS.

Unintentional intraoperative awareness during sufentanil anaesthesia for cardiac surgery.

PURPOSE: The aim of this clinical report is to describe a case of unintentional intraoperative awareness during sufentanil anaesthesia in a patient undergoing elective aortocoronary bypass grafting. CLINICAL FINDINGS: After premedication with morphine (5 mg) and scopolamine (0.2 mg), this 51-yr-old woman received sufentanil (10 micrograms.kg-1), midazolam (4 mg) and isoflurane (0.3-0.4% end-tidal). The patient recalled specific events and discussions which took place in the operating room during surgery. This patient's report was clear and corroborated by operating room personnel. The patient denied having felt pain, anxiety or emotional distress. CONCLUSION: Although awareness during opioid anaesthesia has been previously described with morphine and fentanyl, as far as we know this is the first clinical report of awareness with sufentanil. Given that recent efforts of early extubation in cardiac surgery patients may involve a reduction in the amount of opioid administered, this report serves as a reminder of the ever present potential for this disturbing complication.

Preemptive analgesic effects of steroid anesthesia with alphaxalone in the rat formalin test. Evidence for differential GABA(A) Receptor modulation in persistent nociception.

BACKGROUND: The role of preemptive treatment with volatile and intravenous anesthetics has been examined in previous studies using the rat formalin test. Evidence describing analgesic properties of the gamma-amino butyric acid-ergic (GABAergic) steroid anesthetics, such as alphaxalone, suggest that they may suppress the development of central sensitization to pain. This study examined the preemptive effects of phaxalone in comparison with other GABAergic anesthetics, propofol and pentobarbital. METHODS: The pain behavior of rats was evaluated (using the previously validated weighted scores method of behavioral rating) 15-60 min after subcutaneous hind paw injection of 50 microg 1.5% formalin. In each trial, anesthetics and their respective vehicles were administered by tail-vein injection either 0.5-10 min before or 5 min after, formalin injection. When analgesic effects were observed with any of these agents, further studies were conducted with a GABA(A) receptor antagonist in an attempt to confirm a specific receptor-mediated action of the agent. RESULTS: Alphaxalone pretreatment produced transient analgesia in the early part of phase 2, which was not observed in rats posttreated with alphaxalone. The analgesic effect of alphaxalone was antagonized by picrotoxin, as well. Neither pentobarbital nor propofol showed any analgesic effects at the doses used in our study. CONCLUSIONS: Whereas alphaxalone was shown to produce preemptive analgesia through its action at the GABA(A) receptor, pentobarbital and propofol, which also are known to act at this site, showed no analgesic effects. The diversity of receptor subtypes and functional complexity of GABA(A) receptors is such that steroid anesthetics may have effects that are different from other GABAergic agents. Further research into the role of progesterone metabolites and steroid anesthetics in the prevention of central sensitization may have clinical implications for the treatment of acute or chronic pain.

The introduction of new drugs into anaesthetic practice: a perspective in pharmaceutical development and regulation.

This article reviews the process by which new drugs are introduced into anaesthetic practice with particular emphasis on pharmaceutical development and government regulation. After a brief overview of the drug development process, new trends in drug development are discussed including implementation of pharmacokinetic, pharmacodynamic and toxicokinetic studies in both preclinical and human phases of drug evaluation. A synopsis of the drug regulatory process is provided and, in particular, the problem of unapproved drug use in anaesthesia is discussed. Ethical issues regarding physician-industry interactions are highlighted by examples of conflict of interest in anaesthesia. The processes of drug development and regulation require much effort and cooperation between clinicians, pharmaceutical manufacturers and government regulators to achieve a common goal; the development and utilization of safe and effective drugs. A fundamental understanding of these processes may further facilitate optimal drug utilization and the active involvement of anaesthetists in the drug development process.

Monitoring complication due to a pulsatile femoral vein from tricuspid regurgitation.

This clinical report illustrates a monitoring complication due to a pulsatile femoral vein from tricuspid regurgitation. In this case, the femoral vein of a patient was inadvertently cannulated and exhibited a pulsatile tracing which was mistaken for an arterial pressure tracing. This led to the initial inappropriate use of vasopressors which actually augmented the pulsatility and delayed detection of the error. Although this may be a rare occurrence, the clinician should be aware of its possibility when using invasive monitoring in a patient with tricuspid regurgitation.