Advances in analgesic drug design and delivery: a current survey.
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Analgesics↗
Biomedical subjects
Daniel B Carr
Publications and source records attributed to Daniel B Carr.
Is RNA-laden p24 capsid protein a vector for HIV?
The consensus HIV infection pathway, although well supported by abundant experimental evidence, fails to account for infection of cells (e.g., neurons) that lack CD4 and/or coreceptors. We present the hypothesis that p24 capsid protein laden with RNA may be an alternative virulent agent. A novel mechanism of HIV infection may involve binding of the capsid with membrane receptors, followed by internalization of the capsid-receptor complex. This new pathway suggests novel strategies for antiviral pharmacotherapy.
Capsid Proteins↗
Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study.
Few placebo-controlled trials have investigated the treatment of breakthrough pain (BTP) in patients with chronic pain. We evaluated the efficacy and safety of intranasal ketamine for BTP in a randomized, double-blind, placebo-controlled, crossover trial. Twenty patients with chronic pain and at least two spontaneous BTP episodes daily self-administered up to five doses of intranasal ketamine or placebo at the onset of a spontaneous BTP episode (pain intensity > or =5 on a 0-10 scale). Two BTP episodes at least 48 h apart were treated with either ketamine or placebo. Patients reported significantly lower BTP intensity following intranasal ketamine than after placebo (P < 0.0001) with pain relief within 10 min of dosing and lasting for up to 60 min. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, while seven out of 20 (35%) patients in placebo group did (P = 0.0135). Intranasal ketamine was well tolerated with no serious adverse events. After ketamine administration, four patients reported a transient change in taste, one patient reported rhinorrhea, one patient reported nasal passage irritation, and two patients experienced transient elevation in blood pressure. A side effect questionnaire administered 60 min and 24 h after drug or placebo administration elicited no reports of auditory or visual hallucinations. These data suggest that intranasal administration of ketamine provides rapid, safe and effective relief for BTP.
Administration, Intranasal↗
Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects.
Ultralow doses of naloxone (0.001-0.1 microg/kg) produce analgesia in animal models. However, no clinical study has evaluated the combination of ultralow dose naloxone and morphine using patient-controlled analgesia (PCA). This randomized, double blind controlled study sought to determine if the combination of ultralow dose naloxone and morphine in PCA solutions affects opioid requirements, analgesia, and side effects. Two-hundred and sixty-five patients (18-65 years old) undergoing operations were randomized to receive PCA morphine 1 mg/ml (n=129) or PCA morphine 1 mg/ml plus naloxone 0.6 microg/ml (n=136). We evaluated the numbers of supplemental rescue doses, the cumulative dose of each PCA solution, pain intensity, pain relief, and opioid side effects during the first 24 h after surgery. We found that opioid requirements did not differ significantly between groups. The morphine+naloxone group on average required 0.07 mg more morphine (95% CI -1.1 to 1.3) during the 24 h than the morphine group. Pain intensity levels were also similar in both groups. The morphine+naloxone group had 0.06 units lower (95% CI -0.5 to 0.4) pain intensity levels than the morphine group. The morphine+naloxone group had a lower incidence of nausea and pruritus than the morphine group (P=0.01 for both symptoms). However, the incidence of vomiting, time to tolerate fluids, sedation, and urinary retention were similar between groups (all P values >0.1). The combination of ultralow dose naloxone and morphine in PCA does not affect analgesia or opioid requirements, but it decreases the incidence of nausea and pruritus.
Adolescent↗
Safety and efficacy of intranasal ketamine in a mixed population with chronic pain.
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Administration, Intranasal↗
Pain relief: a universal human right.
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Human Rights↗
Evidence report on the treatment of pain in cancer patients.
Pain associated with cancer is of widespread concern. We conducted a systematic review to evaluate the best available evidence on the efficacy of treatments of cancer-related pain. The sources used were MEDLINE, CancerLit, and the Cochrane Library from 1966 through April 2001, as well as bibliographies of meta-analyses and review articles. We selected randomized controlled trials (RCTs) reporting on cancer pain treatment. We recorded the study characteristics, patient and disease characteristics, treatment comparisons, outcome measures, and results. The methodological quality, applicability, and magnitude of treatment effect for each study were graded. We screened 24 822 titles and selected 213 RCTs to address specific questions. RCTs of cancer pain control often enroll few subjects, have low methodological quality, offer little detail about pain characteristics and mechanisms, and involve heterogeneous interventions and outcomes. Nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, selected adjuvant medications, bisphosphonates, radionuclides, external radiation, palliative chemotherapy, and neurolytic celiac plexus block are each efficacious in relieving cancer pain. However, the retrieved RCTs indicate no difference in the analgesic efficacies of NSAIDs versus other NSAIDs, NSAIDs plus opioids versus NSAIDs alone, or NSAIDs versus opioids. Studies of adjuvant medications and behavioral therapies are too few and varied to synthesize. RCTs of the analgesic effects of corticosteroids were not retrieved in our review, although we did conduct supplemental evidence reviews concerning pain control in oral mucositis, acute herpes zoster, or postherpetic neuralgia. RCTs confirm the efficacy of diverse interventions in relieving cancer pain. The optimal initial and subsequent sequence of choices among analgesic drug types cannot be inferred from the retrieved RCTs. Patient preferences, the relative efficacy of different routes of drug administration, the side effects of analgesics, and the relation of pain control to quality of life have not been studied comprehensively. The quantity and quality of scientific evidence on cancer pain relief compare unfavorably with evidence related to treatment of other high-impact conditions, including cancer itself. One contributor to this gap is the heterogeneity of outcomes instruments employed: of 218 retrieved trials, there were 125 distinct pain outcomes assessed. In the current era of patient-centered care, improving the quality and combinability of trials on cancer pain relief should be a high research priority.
Analgesics, Opioid↗
Hyperalgesia in outpatients with dermal injury: quantitative sensory testing versus a novel simple technique.
OBJECTIVE: Dermal inflammation from many causes may produce a reversible period of hyperalgesia (increased sensitivity to pain perception) or allodynia (pain from innocuous stimuli). Hyperalgesia and allodynia have received relatively little attention in clinical trials of acute pain. We sought to quantitate tactile allodynia and thermal hyperalgesia in outpatients presenting with acute dermal injuries. DESIGN: We performed a randomized clinical trial to compare standard methodology for the assessment of hyperalgesia with two novel simple quantitative techniques. PATIENTS: After Institutional Review Board approval, 40 patients presenting with acute chemical, thermal, mechanical, or infectious skin injury were subjected to a series of tests at the site of injury, an intact mirror site, and a noninjured ipsilateral control site. OUTCOME MEASURES: Quantitative thermal sensory testing (Medoc sensory analyzer) was followed by a 5-second application, in random order, of copper rods preheated in water to 40 degrees C, 43 degrees C, 46 degrees C, and 49 degrees C. Pressure testing was conducted with a 1.25-inch diameter commercially available pressure transducer gauge. RESULTS: The observed pattern of responses was remarkably consistent among testing methods. All challenges with the four different temperatures elicited pain scores on a visual analog scale markedly greater at the injured than at the mirror or control site (P < 0.001 vs control). Pressure discomfort thresholds followed a similar pattern. CONCLUSIONS: We conclude that hyperalgesia is a prominent contributor to discomfort in acute dermal injury and hence is a legitimate therapeutic target. Quantitation of the contribution of thermal hyperalgesia and tactile allodynia and assessment of their management is feasible using simple, rugged, low-cost methods. This inexpensive methodology may be useful in everyday clinical practice as well as in clinical research evaluating pharmacological agents to manage hyperalgesia.
Adolescent↗
The case for pain medicine.
Pain Medicine has its roots in multiple primary specialties and has developed into a discrete specialty with disparate practice styles. Its identity is in flux and is threatened by forces that may fragment this new field before it can set firm roots. The public health crisis of under treated pain parallels medicine's struggle to adequately classify Pain Medicine as a specialty. We review the case for Pain Medicine as a discrete discipline, with specialized knowledge, treatments, training and education. Without recognition of the specialty of Pain Medicine, and resolution of the fragmentation of the field throughout healthcare, medicine's approach to the current problem of under treated pain is likely to continue to be inadequate.
Humans↗
The effect of short-term epidural local anesthetic blockade on urinary levels of substance P in interstitial cystitis.
UNLABELLED: We investigated the effect of epidural local anesthetic blockade on urinary substance P levels in five patients suffering from painful flare-ups of interstitial cystitis. Urine was collected in 24-h intervals commencing at the onset of an epidural bolus of 0.25% bupivacaine followed by maintenance epidural infusions of 0.05% bupivacaine. Substance P was measured by radioimmunoassay. After initiation of the epidural infusion, urinary substance P levels increased and then declined in all patients. All patients reported a decrease in pain intensity. We hypothesize that acute release, followed by depletion, of substance P from bladder sensory nerve endings accounts for the transient increase of peptide levels in urine and may contribute to the decrease in pain intensity during a 3-day epidural infusion. IMPLICATIONS: Substance P levels in urine initially increased and then declined in a series of 5 patients who achieved pain control by epidural local anesthetic infusion during a flare-up of interstitial cystitis.
Anesthesia, Epidural↗
Antihyperalgesic effect of simultaneously released hydromorphone and bupivacaine from polymer fibers in the rat chronic constriction injury model.
We aimed to evaluate the antihyperalgesic efficacy of a combination of hydromorphone (HM) and bupivacaine (BP) delivered via controlled release from a biodegradable cylindrical rod. In vivo studies were performed using a rat model of thermal hyperalgesia induced by chronic constriction injury (CCI) of the sciatic nerve with loose ligatures. Poly(lactic-co-glycolic acid) (PLGA) rods (10 mm length, 1 mm diameter) loaded with HM (5 mg per rod), BP (5 mg per rod) or no drug (placebo) were implanted subcutaneously, in single or dual pairs, adjacent to the constriction injury, immediately after nerve ligation. We evaluated the efficacy of two dose levels for each drug, alone or in combination, in attenuating thermal hyperesthesia over a period of 12 days according to a prevention protocol. Plasma levels of drugs released from the rods and also released in an in vitro simulation were evaluated. In vitro studies demonstrated that drug release is maintained for at least 10 days. HM (5 mg) alone and BP (5 mg) alone did not attenuate hyperalgesia. Their combination provided a significant increase in the paw withdrawal latency as compared to single agents or placebo. When the dose in each group was doubled, implanting four rods, significant attenuation of hyperalgesia was observed. Analyses of rods retrieved after termination of experiments (after 12 days) revealed 30% residual HM and 70% residual BP content. Prolonged delivery of HM and BP alone or in combination via locally applied PLGA rods may offer a feasible alternative to provide long-lasting analgesia.
Analgesics, Opioid↗
Physical functioning: self-report and performance measures are related but distinct.
STUDY DESIGN: Cross-sectional study of 63 patients with chronic low back pain (CLBP). OBJECTIVES: To determine the relationship between the SF-36 physical functioning (PF) scale and physical performance on a modified symptom limited treadmill test, and to determine the effect of disability status and SF-36 mental health (MH) scores on self-reported physical functioning and on physical performance. SUMMARY OF BACKGROUND DATA: Patients with CLBP report low levels of physical functioning. Because self-report measures are influenced by psychosocial factors, such as disability and low MH, a common recommendation is to supplement self-report with objective or physical performance testing. Little information exists regarding whether performance testing is also influenced by disability and low MH. MATERIALS AND METHODS: Patients completed the SF-36 and performed a maximal, symptom-limited, modified treadmill test. Total walking time and heart rate on the treadmill were registered. The effects of disability and low MH on self-report and performance testing were calculated by unpaired Student's t-testing and effect size estimation. RESULTS: A strong relationship between the PF scale of the SF-36 and treadmill walking time was found, but there was little evidence of overlap between these physical functioning domains. Both disability status and low MH had a much larger effect on self-report measures than on physical performance. CONCLUSIONS: Self-report measurements and performance-based assessments provide information about distinct, although related, domains of physical functioning. Disability and low MH are associated with lower SF-36 PF scores. Our results confirm that self-report measures require supplementation with objective performance testing to provide optimal assessment for patients with CLBP.
Activities of Daily Living↗
Core outcome domains for chronic pain clinical trials: IMMPACT recommendations.
OBJECTIVE: 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. METHODS: 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. CONCLUSIONS: 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.
Chronic Disease↗
Agreement between percentage pain reductions calculated from numeric rating scores of pain intensity and those reported by patients with acute or cancer pain.
The use of percentage pain reduction is increasingly used to evaluate the effectiveness of pain treatments, but the degree of agreement between calculated percentage pain reduction (CPPR) as calculated from pre- and post-treatment levels of pain intensity and those reported directly by patients is unknown. Lack of agreement between these two measures could lead to errors in the determination of treatment effectiveness. We aimed to determine the agreement between CPPR and patient-reported percentage pain reduction (PRPPR). Patients with acute or cancer pain were asked to rate their pain intensity on a 0-10 verbal numerical rating scale (NRS) and to estimate the percent pain reduction from baseline pain after analgesic administration. They then received analgesics every 10 min until pain intensity declined to 4/10 or less. To evaluate agreement between CPPR and PRPPR, we computed the concordance correlation coefficient (CCC), which measures both accuracy and precision, and estimated the 95% limits of agreement for the differences between these two measures. 761 adult patients were enrolled. Female, healthy patients with acute pain of severe intensity and high levels of education predominated in the sample. The mean difference between CPPR and PRPPR was -2.6% (95% limits of agreement -12 to 17%). The CCC was 0.56 (accuracy was 0.9 and precision was 0.6). Although CPPR appeared to underestimate PRPPR in the higher range, this trend was not clinically important. The agreement between percentage pain reductions calculated from NRS scores and those estimated by patients did not vary according to gender or age. The good overall agreement between percentage pain reductions calculated from NRS scores and those estimated by patients suggests that these indices may be used interchangeably. The findings of this study extend existing patient-centered pain research and may be applied for the evaluation and comparison of pain treatments.
Acute Disease↗
Side effects of opioids during short-term administration: effect of age, gender, and race.
OBJECTIVE: Little is known about risk factors that increase the risk of development of opioid side effects. Our objective was to evaluate the effect of the type of opioid, age, gender, and race on the incidence of side effects from short-term opioid use. METHODS: A secondary analysis of a retrospective cohort study in 35 community-based and tertiary hospitals was done. There were 8855 black or white subjects aged 16 years and older. Patients received meperidine (INN, pethidine), morphine, or fentanyl as part of their treatment. Measurements were made to assess the presence of nausea and vomiting and respiratory depression. RESULTS: Of the patients, 26% had nausea and vomiting and 1.5% had respiratory depression after opioid administration. After adjustment for opioid dose, route of administration, age, gender, and race, meperidine produced less nausea and vomiting (odds ratio [OR] = 0.7; 95% confidence interval [CI], 0.5-0.8) and less respiratory depression (OR = 0.6; 95% CI, 0.2-0.9) than morphine. The risk of respiratory depression increased with age. Compared with patients aged between 16 and 45 years, those aged between 61 and 70 years had 2.8 times the risk of development of respiratory depression (95% CI, 1.2-6.6); those aged between 71 and 80 years had 5.4 times the risk (95% CI, 2.4-11.8); and those aged older than 80 years had 8.7 times the risk (95% CI, 3.8-20.0). Men had less nausea and vomiting than women (OR = 0.5; 95% CI, 0.4-0.6). White subjects had more nausea and vomiting than black subjects (OR = 1.4; 95% CI, 1.1-1.7). CONCLUSIONS: Meperidine produced fewer side effects than morphine during short-term use. The risk of respiratory depression increases substantially after 60 years of age. Women have nausea and vomiting more often than men. The effect of race deserves further investigation.
Adolescent↗
What decline in pain intensity is meaningful to patients with acute pain?
Despite widespread use of the 0-10 numeric rating scale (NRS) of pain intensity, relatively little is known about the meaning of decreases in pain intensity assessed by means of this scale to patients. We aimed to establish the meaning to patients of declines in pain intensity and percent pain reduction. Upon arrival to the postanesthesia care unit, postsurgical patients rated their baseline pain intensity on both a 0-10 NRS and on a 4-point verbal scale. Patients whose NRS was higher than 4/10 received intravenous opioids until their pain intensity declined to 4/10 or lower. During opioid titration, patients were asked every 10 min to rate pain intensity on a NRS and to indicate the degree of pain improvement on a 5-point Likert scale from 'no improvement' to 'complete pain relief'. Seven hundred adult patients were enrolled. For patients with moderate pain, a decrease of 1.3 units (20% reduction) corresponded to 'minimal' improvement, a decrease of 2.4 (35% reduction) to 'much' improvement, a decrease of 3.5 units (45% reduction) corresponded to 'very much' improvement. For patients with severe pain, the decrease in NRS pain score and the percentage of pain relief had to be larger to obtain similar degrees of pain relief. The change in pain intensity that is meaningful to patients increases as the severity of their baseline pain increases. The present findings are applicable in the clinical setting and research arena to assess treatment efficacy.
Acute Disease↗
A comparison of multimodal perioperative analgesia to epidural pain management after gastric bypass surgery.
We compared pain intensity, analgesic consumption, patient satisfaction, and length of stay in 114 patients undergoing gastric bypass surgery under general anesthesia. Patients were randomized to incisional local anesthetic infiltration plus postoperative patient-controlled analgesia (Group A), epidural anesthesia and analgesia (Group B), or postoperative patient-controlled analgesia (Group C). All received perioperative nonsteroidal antiinflammatory drugs. Age, sex, body mass index, length of stay, and patient satisfaction were equivalent in all groups. Pain at time 0 and 36 h was the smallest in Group B, greater in Group A, and greatest in Group C. Pain scores in a subset of Group A were lower at all times than in Groups B and C, but this difference was significant only at 0, 12, and 36 h. In responders, infiltration analgesia as part of a multimodal regimen offers a simple, safe, and inexpensive alternative to epidural pain control.
Adolescent↗
Combination spinal analgesic chemotherapy: an additional clinical trial of opioid plus local anesthetic.
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Analgesia, Epidural↗