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Enriched enrolment, randomised withdrawal (EERW) pain trials select, before randomisation, patients who respond by demonstrating a predetermined degree of pain relief and acceptance of adverse events. There is uncertainty over the value of this design. We report a systematic review of EERW trials in chronic noncancer pain together with a critical appraisal of methods and potential biases in the methods used and recommendations for the design and reporting of future EERW trials. Electronic and other searches found 25 EERW trials published between 1995 and June 2014, involving 5669 patients in a randomised withdrawal phase comparing drug with placebo; 13 (median, 107 patients) had a randomised withdrawal phase of 6 weeks or less, and 12 (median, 334) lasted 12 to 26 weeks. Risks of bias included short duration, inadequate outcome definition, incomplete outcome data reporting, small size, and inadequate dose tapering on randomisation to placebo. Active treatment was usually better than placebo (22/25 trials). This review reduces the uncertainty around the value of EERW trials in pain. If properly designed, conducted, and reported, they are feasible and useful for making decisions about pain therapies. Shorter, small studies can be explanatory; longer, larger studies can inform practice. Current evidence is inadequate for valid comparisons in outcome between EERW and classical trials, although no gross differences were found. This systematic review provides a framework for assessing potential biases and the value of the EERW trials, and for the design of future studies by making recommendations for the conduct and reporting of EERW trials.

There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

OBJECTIVES To evaluate the efficacy and tolerability of 4 doses of GW406381, a cyclooxygenase-2 inhibitor, compared with placebo in a standard model of acute inflammatory pain. METHODS This randomized, double-blind, placebo-controlled, single-center study compared single doses of GW406381 (10 to 70 mg) or naproxen sodium 550 mg with placebo in patients after extraction of 2 or more partially bony impacted third molar teeth. A total of 300 patients were randomized (50 per group). The primary efficacy variable was the pain relief intensity difference score at each time point, which was calculated as the sum of the pain intensity difference and pain relief categorical scores at each time point. Each treatment was compared with placebo at each time point using an ordered hierarchical approach with closed testing procedures and last observation carried forward imputation methods. RESULTS Pain relief intensity differences from placebo were statistically significant beginning at 1.5 hours postdosing for GW406381 70 and 50 mg and at 2-hour postdosing for GW406381 25 and 10 mg. The median time to onset of analgesia was 71 minutes for GW406381 50 mg, 72 minutes for GW406381 70 mg, and 36 minutes for naproxen. The median duration of analgesia was 5.9 hours for GW406381 50 mg, 7.9 hours for GW406391 70 mg, and 11.3 hours for naproxen. All treatments were well tolerated. DISCUSSION GW406381 50 and 70 mg demonstrated clinically meaningful analgesia in this acute pain setting, although the onset of analgesia was greater than 1 hour.

The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. We describe the use of multiple endpoints in the design, analysis, and interpretation of pain clinical trials, and review available strategies and methods for addressing multiplicity. To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.

This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and tolerability of lamotrigine added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic in patients whose neuropathic pain was inadequately controlled with these medications. Patients with neuropathic pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy, who had a mean weekly pain score ≥4 on an 11-point numerical rating scale, were randomized to receive a flexible dose of lamotrigine 200, 300, or 400mg daily (n=111) or placebo (n=109) for up to 14 weeks (including eight weeks of dose escalation) in addition to their prestudy regimen of gabapentin, a tricyclic antidepressant, or a nonopioid analgesic. No statistically significant difference in the mean change in pain-intensity score from baseline to Week 14 (primary endpoint) was detected between lamotrigine and placebo (P=0.67). Differences between lamotrigine and placebo were not statistically significant for secondary efficacy assessments, including mean changes from baseline in the Short-Form McGill Pain Questionnaire, the Neuropathic Pain Scale, rescue medication use, and the percentages of patients rated as much improved or very much improved at the end of treatment on the Clinician Global Impression of Change scale and the Patient Global Impression of Change scale. Lamotrigine was generally well tolerated. Lamotrigine (up to 400mg/day) added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic did not demonstrate efficacy as an adjunctive treatment of neuropathic pain but was generally safe and well tolerated.

a University of Washington, Seattle, WA 98195, USA b University of Rochester School of Medicine and Dentistry, Rochester, NY, USA c United States Food and Drug Administration, Rockville, MD, USA d Northwestern University, Chicago, IL, USA e Johnson and Johnson, Raritan, NY, USA f AstraZeneca, Wilmington, DE, USA g University of California San Diego, La Jolla, CA, USA h Merck and Company, Blue Bell, PA, USA i University of Texas, M.D. Anderson Cancer Center, USA j American Chronic Pain Association, Rocklin, CA, USA k Allergan, Inc, Irvine, CA, USA l National Institute of Dental and Craniofacial Research, Bethesda, MD, USA m University of Pennsylvania, Philadelphia, PA, USA n Johns Hopkins University, Baltimore, MD, USA o University Health Network and University of Toronto, Toronto, Canada p Novartis Pharmaceuticals, East Hanover, NJ, USA q VA Connecticut Healthcare System, West Haven, CT, USA r Yale University, New Haven, CT, USA s Celgene Corporation, Warren, NJ, USA t Pfizer Global Research and Development, Ann Arbor, MI, USA u Dalhousie University, Halifax, Nova Scotia, Canada v London Regional Cancer Centre, London, Ont., Canada

To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment.Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain.There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.

Several lines of evidence suggest that neuropathic pain is mediated in part by an increase in the density of voltage-sensitive sodium channels in injured axons and the dorsal root ganglion of injured axons. The purpose of this study was to examine the safety, analgesic efficacy, and tolerability of oral 4030W92 (a new novel sodium channel blocker) in a group of subjects with chronic neuropathic pain. This study used a randomized, double-blind, placebo-controlled, crossover design in 41 subjects with neuropathic pain with a prominent allodynia. Each subject received a 2-week course of 4030W92 (25 mg/day) and placebo separated by a 2-week washout period. At baseline, postdose day 1, day 7, and day 14, the following were measured: (1) spontaneous and evoked pain scores, (2) dynamic and static allodynia mapping, (3) Short Form McGill Pain Questionnaire, and (4) blood sample for 4030W92 assay. At baseline and day 14 the following were measured: (1) thermal testing in the painful area, (2) Medical Outcomes Study Short Form 36 Questionnaire, and (3) patient global satisfaction. Allodynia severity was significantly lower (P =.046) on treatment day 1, postdose for 4030W92 compared to placebo. However, this was not maintained on treatment day 7 or 14. The area of static allodynia was significantly smaller (P =.03) on treatment day 7 for 4030W92 compared to placebo. However, this was not maintained to treatment day 14. There was no significant effect of 4030W92 on any other efficacy measure. Side effects were minimal. 4030W92, at 25 mg/day, produced a nonsignificant reduction in pain without treatment limiting side effects. The maximum analgesic effect of this drug remains unknown. © 2002 by the American Pain Society

The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. We describe the use of multiple endpoints in the design, analysis, and interpretation of pain clinical trials, and review available strategies and methods for addressing multiplicity. To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.

A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed. Perspective Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.

To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p < or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.

Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation, which can be regulated by systemically administered sodium channel blockers. We have extended these preclinical studies to the human volunteers by examining the effects of lamotrigine and 4030W92, two structurally related voltage-sensitive sodium channel antagonists, on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. Fifteen healthy subjects received 4030W92, lamotrigine, and placebo in a randomized order using double-blinded crossover design methodology in three sessions each separated by a 7-day washout period. In each session, baseline neurosensory testing was performed on the volar aspect of the subject's left forearm. Subjects were then dosed with either lamotrigine (300 mg), 4030W92 (100 mg), or placebo, followed 2 h later by capsaicin (100 microg) injected intradermally on the volar aspect of the left forearm. Pain scores, blood pressure, heart rate, and respiratory rate were measured at the time of injection and every 5 min for 15 min. Fifteen minutes after the capsaicin injection, the hyperalgesic area was determined by von Frey hair, stroking, and heat; the flare response was outlined; and neurosensory testing again was performed halfway between the edge of the hyperalgesic area and the capsaicin injection site. While capsaicin significantly decreased the hot pain and VF pain thresholds, oral lamotrigine and 4030W92 failed to alter this response to capsaicin, relative to placebo treatment. Similarly, oral lamotrigine or 4030W92 did not alter the pain scores reported from mechanical pain stimuli at any time postcapsaicin. This study showed a lack of effect of two structurally similar sodium channel antagonists on a human experimental pain model using intradermal capsaicin, which is consistent with other studies on the effects of sodium channel antagonists of capsaicin-induced pain and hyperalgesia. This lack of effect stands in contrast to reported effects of sodium channel antagonists on preclinical models of cutaneous hyperalgesia or effects of lamotrigine on clinical neuropathic pain.

Background: Nerve injury results in increases in spinal glutamate, which opens the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site must be occupied for the channel to open. GV196771 is a selective antagonist of the glycine-binding site of the NMDA ionophore. Objective: To determine the efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of-concept study. Methods: With informed consent, 63 subjects (31 placebo, 32 GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, or peripheral nerve injury), a visual analogue score averaging ≥30 mm during the screening period, and a well-defined primary area of mechanical allodynia were recruited for the study. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study design was utilized. Subjects came to the research center for a total of five visits over a 21-day period, which consisted of a 14-day treatment period followed by a 7-day washout period. Spontaneous and evoked pain scores, mechanical sensory testing, quantitative sensory testing, Short Form McGill Pain Questionnaire, patient global satisfaction, and safety assessments were made during the study. Results: There was no significant effect of GV196771 on spontaneous or evoked pain, quantitative sensory testing, or patient global satisfaction. There was a significant effect of GV196771 on the area of dynamic and static allodynia on days 7 and 14. The overall incidence of adverse events during treatment was similar for GV196771 (56%) and placebo (71%). The incidence of drug-related adverse events during treatment was higher for placebo (42%) than GV196771 (28%). Conclusions: Although the glycine antagonists show anti-hyperalgesic action in animal models of neuropathic pain, GV196771 does not appear to be an effective treatment in subjects with chronic neuropathic pain. This may be due to insufficient penetration of GV196771 to central sites of action, differences between the human and animal glycine receptors, or differences between neuropathic pain in animal models and humans.

Background Atracurium consists of a mixture of ten stereoisomers. One of these isomers, 51W89, is a potent intermediate-acting nondepolarizing neuromuscular blocking agent. Its ED95 is 0.05 mg.kg-1 in patients receiving nitrous oxide/opioid anesthesia. In preclinical trials, 51W89 did not show evidence of histamine release in cats at doses up to 80 times the human ED95. This study was undertaken to determine the cardiovascular effects and histamine-releasing properties of 51W89 in patients undergoing elective surgical procedures. Methods Sixty patients, ASA physical status 1 or 2, anesthetized with nitrous oxide/fentanyl/thiopental were studied. Patients received either 2 times the ED95 of atracurium or 51W89 or 4 or 8 times the ED95 of 51W89 as a rapid intravenous bolus under stable anesthesia, before surgical stimulation. Blood pressure and heart rate were measured by oscillometry and the electrocardiogram in patients receiving 2 times the ED95 of 51W89 or atracurium and by an intraarterial catheter and a tachograph triggered by the arterial pulse waveform in patients receiving 4 or 8 times the ED95 of 51W89. Maximal blood pressure and heart rate changes during the 5 min after administration of the muscle relaxant were recorded. Venous blood samples were obtained before the administration of relaxant and at 2 and 5 min after the administration of relaxant for determination of plasma histamine concentrations by radioenzymatic assay. Results Maximal blood pressure and heart rate changes in all groups of patients receiving 51W89 were small and similar to those observed in patients receiving 2 times the ED95 of atracurium. The mean maximum percent changes (+/- SE) in heart rate and mean arterial pressure were -0.6 +/- 1.5 and 0.4 +/- 2.5, respectively, in the group receiving 2 times the ED95 atracurium; -1.3 +/- 3.3 and 2.3 +/- 4.4, respectively, in the group receiving 2 times the ED95 51W89; -2.6 +/- 1.0 and 2.6 +/- 1.5, respectively, in the group receiving 4 times the ED95 51W89; and -2.4 +/- 1.5 and -1.0 +/- 1.3, respectively, in the group receiving 8 times the ED95 51W89. No patient developed a decrease in blood pressure > or = 20% or an increase in heart rate > or = 20% that was attributable to muscle relaxant administration. There was no dose-related change in plasma histamine concentration associated with the administration of 51W89. One patient in the study developed transient facial flushing after the administration of atracurium. Conclusions 51W89 is a benzylisoquinolinium-type, nondepolarizing muscle relaxant that does not affect plasma histamine concentrations. No cutaneous flushing or clinically important cardiovascular effects were noted after rapid injection of doses up to and including 8 times its ED95 (0.4 mg.kg-1) in healthy patients undergoing elective surgical procedures.

Background Atracurium is a mixture of ten stereoisomers. 51W89, one of these isomers, is a potent nondepolarizing intermediate-duration neuromuscular blocking agent. Preclinical studies have shown 51W89 to be significantly more potent than atracurium but with a similar neuromuscular blocking profile. This study was undertaken to establish the neuromuscular blocking potency and pharmacodynamics of 51W89 in patients undergoing elective surgical procedures. Methods Ninety-nine ASA physical status 1 or 2 patients undergoing elective surgical procedures under nitrous oxide/opioid/barbiturate anesthesia were studied. The neuromuscular blocking effect of 51W89 was assessed after administration of bolus doses from 0.015 to 0.4 mg/kg, as well as during and after continuous infusions from 11 to 249 min in length. Results The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.048 mg/kg. At 0.10 mg/kg, maximum block developed within 5.2 +/- 0.3 min, and recovery to 95% twitch height occurred 64.4 +/- 3.9 min after injection. At 0.4 mg/kg, onset was 1.9 +/- 0.1 min, and 95% recovery developed within 121.0 +/- 5.9 min. Comparative recovery indexes from 5% to 95% or from 25% to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.4 mg/kg (means ranged from 29.6 to 32.3 min and from 12.6 to 14.3 min, respectively). The average infusion rate necessary to maintain approximately 95% twitch suppression was 1.35 micrograms/kg/min. Recovery indexes from infusions were 5-95% 33.2 +/- 1.8 min and 25-75% 15.0 +/- 0.6 min, not differing significantly from recovery indexes from single bolus doses. Twenty-five patients received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at twitch height recovery of between 6% and 21%. Antagonism to 95% control twitch height developed within 6.8 +/- 0.3 min, and the neostigmine-accelerated 25-75% recovery index was 2.8 +/- 0.2 min. Conclusions 51W89 is a potent nondepolarizing neuromuscular blocking agent that shows noncumulative intermediate-duration neuromuscular blocking pharmacodynamics.

Background Atracurium consists of a mixture of ten stereoisomers. One of these isomers, 51W89, is a potent intermediate-acting nondepolarizing neuromuscular blocking agent. Its ED95 is 0.05 mg.kg-1 in patients receiving nitrous oxide/opioid anesthesia. In preclinical trials, 51W89 did not show evidence of histamine release in cats at doses up to 80 times the human ED95. This study was undertaken to determine the cardiovascular effects and histamine-releasing properties of 51W89 in patients undergoing elective surgical procedures. Methods Sixty patients, ASA physical status 1 or 2, anesthetized with nitrous oxide/fentanyl/thiopental were studied. Patients received either 2 times the ED95 of atracurium or 51W89 or 4 or 8 times the ED95 of 51W89 as a rapid intravenous bolus under stable anesthesia, before surgical stimulation. Blood pressure and heart rate were measured by oscillometry and the electrocardiogram in patients receiving 2 times the ED95 of 51W89 or atracurium and by an intraarterial catheter and a tachograph triggered by the arterial pulse waveform in patients receiving 4 or 8 times the ED95 of 51W89. Maximal blood pressure and heart rate changes during the 5 min after administration of the muscle relaxant were recorded. Venous blood samples were obtained before the administration of relaxant and at 2 and 5 min after the administration of relaxant for determination of plasma histamine concentrations by radioenzymatic assay. Results Maximal blood pressure and heart rate changes in all groups of patients receiving 51W89 were small and similar to those observed in patients receiving 2 times the ED95 of atracurium. The mean maximum percent changes (+/- SE) in heart rate and mean arterial pressure were -0.6 +/- 1.5 and 0.4 +/- 2.5, respectively, in the group receiving 2 times the ED95 atracurium; -1.3 +/- 3.3 and 2.3 +/- 4.4, respectively, in the group receiving 2 times the ED95 51W89; -2.6 +/- 1.0 and 2.6 +/- 1.5, respectively, in the group receiving 4 times the ED95 51W89; and -2.4 +/- 1.5 and -1.0 +/- 1.3, respectively, in the group receiving 8 times the ED95 51W89. No patient developed a decrease in blood pressure > or = 20% or an increase in heart rate > or = 20% that was attributable to muscle relaxant administration. There was no dose-related change in plasma histamine concentration associated with the administration of 51W89. One patient in the study developed transient facial flushing after the administration of atracurium. Conclusions 51W89 is a benzylisoquinolinium-type, nondepolarizing muscle relaxant that does not affect plasma histamine concentrations. No cutaneous flushing or clinically important cardiovascular effects were noted after rapid injection of doses up to and including 8 times its ED95 (0.4 mg.kg-1) in healthy patients undergoing elective surgical procedures.