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Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients.

OBJECTIVES: To estimate the frequency of acute withdrawal syndrome related to the administration of analgesic and sedative medications in mechanically ventilated adult intensive care unit (ICU) patients; to identify associated clinical factors. DESIGN: Retrospective review of medical records. SETTING: An adult trauma/surgical ICU in an urban Level I trauma center. PATIENTS: Twenty-eight mechanically ventilated adult trauma/ surgical ICU patients requiring >7 days of ICU care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily doses of all opioid, sedative, hypnotic, and major tranquilizer drugs administered to each patient were measured, as was duration of ICU stay, duration of mechanical ventilation, and duration of the administration of analgesic, sedative, and neuromuscular blocking agents (NMBAs) for each patient. All opioids and benzodiazepines were converted to their respective fentanyl and lorazepam equivalent units based on potency and bioavailability. Calculation of the weaning rate for each patient during tapering from opioid and benzodiazepine medications was performed. The presence or absence of acute withdrawal syndrome was identified for each patient. Nine (32.1%) patients developed acute withdrawal syndrome potentially related to the administration of analgesic or sedative medications. Patients in the withdrawal group received significantly higher mean daily (p = .049) and peak (p = .032) doses of fentanyl equivalents, as well as higher mean daily lorazepam equivalents (p = .049) compared with patients not experiencing withdrawal. Patients in the withdrawal group were also significantly more likely to have received neuromuscular blocking agents (p = .004) or propofol (p =.026) for >1 day during ICU admission compared with patients not experiencing withdrawal. Duration of mechanical ventilation (p = .049), benzodiazepine therapy (p = .048), and propofol therapy (p = .049) was also significantly longer in the group experiencing withdrawal. Withdrawal patients received a significantly lower mean daily dose of haloperidol (p = .026). There was a significant association between the development of withdrawal syndrome and the presence of ARDS (p = .017). Finally, the slopes of the lines representing opioid and benzodiazepine drug weaning were more steep for the withdrawal group, although these results did not achieve statistical significance. CONCLUSIONS: These results suggest that mechanically ventilated adult patients with extended ICU care (> or =7 days) who receive large doses of analgesic and sedative medications are at risk for acute withdrawal syndromes during drug weaning. The association between ARDS and withdrawal syndrome, combined with the observation that withdrawal syndromes were also associated with the use of neuromuscular blocking agents and prolonged mechanical ventilation, suggests that patients with ARDS may be more likely to receive high doses of analgesic and sedative medications, and are therefore at increased risk for withdrawal syndrome.

Acute Disease↗

Analgesics and osteoarthritis: are treatment guidelines reflected in clinical practice?

Osteoarthritis (OA) treatment is complex and multifactorial, with pharmacological regimens requiring sufficient flexibility to be adapted to individual disease progression, flare ups, and response to treatment. Coexisting conditions are common and can lead to problems regarding polypharmacy. Several guidelines have been published for the management of OA pain. While differences exist, most recommend paracetamol as the initial oral drug for OA, based on its efficacy, tolerability, and cost; in patients who respond inadequately to paracetamol, supplementary or replacement analgesics should be recommended. This article considers the reality of analgesic use for OA in clinical practice and the extent to which guidelines are followed both in primary and secondary care. An international survey of rheumatologists (n = 610) found that paracetamol was recommended as first-choice analgesic for OA by 82% of those surveyed. Similarly, in a survey of French GPs, 90% of those surveyed recommended paracetamol first line; NSAIDs were recommended more frequently for stronger pain relief but were also recommended alongside paracetamol as a first-line treatment of mild to moderate pain by 43% of GPs. Finally, a UK patient survey, conducted at a London hospital (n = 200), found that 64% of patients were taking more than 1 drug for treatment of painful OA of the knee or hip; 76% were taking paracetamol and 40% were taking an NSAID. A further 39% had used an NSAID in the past but switched treatment, primarily due to side effects. These findings reinforce the case for the simple analgesic paracetamol to be seen as the cornerstone of pharmacological OA treatment, both as a first-line analgesic and as a foundation to which additional treatment modalities, including NSAIDs, can be added if and when necessary.

Acetaminophen↗

The 2002 Lindberg Award. PRN vs regularly scheduled opioid analgesics in pediatric burn patients.

Very little has been published on treating acute pain in children younger than the age of 3 for burns or any other trauma etiology. This study prospectively monitored the pain behavior and opioid analgesic intake of 31 pediatric burn patients (mean age = 23.71 months; SD = 15.75). Twelve of those children were randomized to conditions in which they either received opioid analgesics pro re nata (ie, as needed, pain contingent) or on a regular basis. The two groups did not show differences in demonstrable pain but, interestingly, they received equivalent does of opioid analgesics. As such, the pro re nata group was likely medicated largely on a regularly scheduled basis. For most of the remaining (nonrandomized) subjects, physicians ordered regularly scheduled opioid analgesics, suggesting that this practice has become largely institutionalized in the study setting. Information on pediatric opioid analgesic dosing and pain measurement strategies for nonverbal subjects can be derived from the findings.

Acute Disease↗

Analgesic use in children with acute abdominal pain.

STUDY OBJECTIVE: To determine the frequency of analgesic use in children (5 to 17 years inclusive) who present to a pediatric emergency department with acute abdominal pain. METHODS: A retrospective medical record review of patients presenting to a children's hospital over a 1-year period with a chief complaint of abdominal pain and subsequently referred to the pediatric surgical service. The records were reviewed to determine emergency department analgesic use, patient disposition, and laparotomy rate. RESULTS: Two hundred ninety patients met our inclusion criteria. Of the patients seen initially by emergency physicians, 14.3% received analgesics, while those seen directly by the surgical service received analgesia 15.4% of the time. The laparotomy rate for the 290 patients was 46.6%. CONCLUSIONS: Analgesic use in children who present to the emergency department with acute abdominal pain and require a surgical consultation was very low, although half required a laparotomy. Prospective studies are needed to determine the efficacy and safety of analgesic use in this setting.

Abdominal Pain↗

Analgesic use in intubated patients during acute resuscitation.

BACKGROUND: Pain relief can often be overlooked during a busy trauma resuscitation, especially in patients who are intubated. We sought to investigate qualitative and quantitative aspects of analgesic use in intubated patients during the acute phase of resuscitation. METHODS: We evaluated a retrospective cohort of consecutive adult patients who were intubated during the acute trauma resuscitation (first 6 hours) from January 2001 to May 2002 at a Level I trauma center in the United States. Patient demographics, injuries, vital signs, medications, trauma bay procedures, and disposition status were analyzed. Analgesia was recorded as the type of analgesic, route of administration, elapsed time to receive the first analgesic, total dosage, and time intervals between two successive doses. Fisher's exact test, chi test, and ANOVA were used to analyze data. RESULTS: A total of 120 patients were included. Sixty-one (51%) patients received analgesia during their stay in the emergency department. Using logistic regression analysis, patients who more likely to receive analgesia were those who did not require immediate surgical operation and were transferred to the intensive care unit (odds ratio [OR]=3.91; 95% CI=1.75-8.76) and those who were admitted during the hours of 8 am to 6 pm (OR=3.17; CI=1.40-7.16). Among those patients receiving analgesia, 30 (25%) patients received analgesia within 30 minutes upon arrival. The mean time of receiving the first analgesia dose was 57 minutes. The average morphine equivalent dose given to the patients was 15.7 mg. The most frequently given single dose was 100 mug of intravenous fentanyl. Most of the analgesics (37%) were given between 30 to 60 minutes apart. CONCLUSION: Our findings suggest that patients who are intubated during the acute resuscitation probably receive inadequate analgesia. The inadequacy appears to be in the timing and repetition of administration, rather than the dose. Patients who were transferred early to the intensive care unit were more likely to receive analgesics.

Acute Disease↗

End-stage renal disease and non-narcotic analgesics: a case-control study.

1. To assess the risk of end-stage renal disease (ESRD) associated with the regular use of three classes of non-narcotic analgesics, we performed a case-control study of 340 patients with ESRD on a haemodialysis maintenance program and 673 hospital controls. 2. The overall odds ratio estimate for non-narcotic analgesics taken at least every other day for 30 days or longer before the first symptom of renal disease was 2.89 (95% CI, 1.78 to 4.68). 3. The risk increased in relation to the use duration. 4. The previous regular consumption of combinations containing phenacetin was strongly associated with ESRD (odds ratio, 19.05; 95% CI, 2.31 to 157.4). The odds ratio for previous regular consumption of salicylates was 2.54 (95% CI, 1.24 to 5.20) and for pyrazolones 2.16 (95% CI, 0.87 to 5.32). 5. An analysis for possible confounding by a history of repeated headaches, arthritis, kidney stones, hypertension, and diabetes did not alter the results. 6. The odds ratio estimates for different pathological subgroups of ESRD patients in relation to previous use of any non-narcotic analgesic were glomerulonephritis. 10.57 (95% CI, 1.25 to 89.0), interstitial nephritis, 3.33 (95% CI, 1.21 to 9.17), cystic kidney disease, 0.71 (95% CI, 0.25 to 1.97), and unknown, 5.15 (95% CI, 2.29-11.57). 7. The results of this study suggest that the regular consumption of analgesics should be routinely considered as a risk factor for any non-congenital cause of chronic renal failure. They also suggest that the risk of ESRD associated with the regular consumption of phenacetin is much higher than the risk associated with other non-narcotic analgesics.

Adolescent↗

Concomitant use of analgesics and psychotropics in home-dwelling elderly people-Kuopio 75 + study.

AIMS: To investigate the extent of concomitant use of analgesic and psychotropic medicines among home-dwelling elderly people aged at least 75 years in Finland. METHODS: This was a population-based study in Finland, performed as part of Kuopio 75 + study focusing on the clinical epidemiology of diseases, medication and functional capacity. A random sample of 700 persons was drawn from the total population of the city of Kuopio, eastern Finland, aged 75 years on January 1, 1998 (n = 4518). Ninety-nine persons could not be examined and 78 were living in long-term institutions, so that the number of home-dwelling elderly persons amounted to 523. A trained nurse interviewed the participants about their use of medicines, and a geriatrician examined their overall physical and mental status. Dementia and depression were diagnosed according to the DSM IV criteria. Both regular and irregular prescribed and nonprescribed drug use was recorded. RESULTS: Every fourth elderly person (27.2%) used analgesics and psychotropics concomitantly, this use becoming twice as common with advancing age (19.6% in the age group 75-79 years, 38.2% among the oldest, aged 85 + years). Concomitant use of psychotropics and opioids also became more common with increasing age (2.8% in age group 75-79 years and 9.6% in the oldest group, aged 85 + years). The use of opioids was nearly twice as common among concomitant users (19.7%) than among those using only analgesics (11.3%). Concomitant users suffered from interfering daily pain and daily pain at rest more commonly than nonusers of analgesics. Depression, sleeping problems and polypharmacy were more common among the concomitant users, who had also had more hip fractures than the rest. CONCLUSIONS: Concomitant use of analgesics and psychotropics becomes more common with advancing age and is a potential risk factor for adverse drug effects.

Age Factors↗

Do codeine and caffeine enhance the analgesic effect of aspirin?--A systematic overview.

OBJECTIVE: To assess whether codeine and caffeine enhance the analgesic effect of aspirin in post-operative pain. METHOD: Systematic overview of the literature and meta-analysis of published randomized controlled trials (RCTs). RESULTS: Codeine 60 mg leads to a small increase in the analgesic effect of 650 mg of aspirin when total pain relief score (TOTPAR%) is used as a efficacy end-point. This increased effect was not seen when sum of pain intensity (SPID%) and proportions of patients responding with moderate to excellent pain relief were used as outcome measures. Caffeine did not enhance the analgesic effect of aspirin. CONCLUSION: Codeine 60 mg may produce a small increase in the analgesic effect of aspirin 650 mg. However, this effect is not clinically meaningful. Caffeine has no adjuvant analgesic effect. At over-the-counter (OTC) doses, caffeine and codeine are not useful in aspirin formulations.

Analgesia↗

An in vitro investigation of the effect of some analgesics on human enamel.

The sale of over-the-counter pain relief medication has increased dramatically in recent years, and typically amounts to several hundred thousands of pounds per year in the UK. Many soluble analgesic preparations contain citric acid, and it has been suggested that these formulations may cause dental erosion. The aim of this study was to investigate the effect of some over-the-counter analgesics on tooth surface loss from human enamel. Six commonly available analgesics were chosen for this study and the effect of immersing unerupted human enamel was examined using non-contact optical profilometry. Two of the six analgesics investigated caused no detectable erosion (Boots soluble aspirin and Anadin Extra). Three caused statistically significant enamel erosion, but this was very slight and is thought to be clinically insignificant (Alka Seltzer, Panadol and Solpadeine). Only one analgesic caused possible potentially clinical significant enamel erosion. Further studies are needed to determine whether Aspro causes clinically significant enamel erosion.

Analgesics, Non-Narcotic↗

Factors associated with analgesic and psychotropic medications use by community-dwelling older people with chronic pain.

OBJECTIVE: The present study sought to examine use prevalence and factors associated with use of analgesic and psychotropic medications in community-dwelling older people with chronic non-malignant pain. METHOD: The study group comprised 193 community-dwelling older people with daily chronic non-malignant pain who were selected from a random sample of 1,000 older people in Melbourne. RESULTS: The use prevalence for the study group was 63% for analgesics and 39% for psychotropic medications, which is higher than the general older population without chronic pain (p < 0.00001). More women with chronic pain used analgesics, while psycho-social factors such as problems with sleeping and living at home alone were found to be associated with an increased use of psychotropic medications. CONCLUSION: A high proportion of community-dwelling older people with chronic non-malignant pain use analgesic and psychotropic medications. IMPLICATIONS: These findings provide the basis for further investigation into the level and appropriateness of analgesic and psychotropic medication use by older people with chronic pain.

Aged↗

THE ANALGESIC PROPERTIES OF SUB-ANAESTHETIC DOSES OF ANAESTHETICS IN THE MOUSE.

Trichlorethylene in a sub-anaesthetic concentration (0.5% v/v in oxygen) has an analgesic effect on mice, which develops slowly and reaches a maximum roughly equivalent to that produced by 5 mg/kg of methadone hydrochloride given by intraperitoneal injection. Ethyl chloride causes analgesia in sub-anaesthetic concentrations (3%) but is much less potent than trichlorethylene. Halothane (0.75%) produces slight but definite analgesia. Cyclopropane and diethyl ether have no appreciable analgesic effect. Concentrations of nitrous oxide (up to 90%) in oxygen lack any observable analgesic action on the mouse. Trichlorethylene is considerably potentiated by nitrous oxide, its anaesthetic rather than its analgesic action being affected. Nitrous oxide (40%) potentiates the analgesic rather than the anaesthetic action of halothane (0.75%). However, increasing the concentration of nitrous oxide to 60% causes the anaesthetic action of halothane to predominate.

Analgesia↗

Studies on the receptors involved in the action of the various agents in the phenylbenzoquinone analgesic assay in mice.

1. Tolerance to the activity of several narcotic analgesics (morphine, levorphanol, and methadone) and several narcotic-antagonist analgesics (pentazocine, cyclazocine, and nalorphine) was studied in the mouse phenylbenzoquinone stretching test. Virtually complete tolerance was induced by chronic treatment with each of the narcotic agents, while no apparent tolerance was induced by the narcotic antagonists.2. In morphine-tolerant mice there was a high degree of cross-tolerance to the effects of not only the other narcotic drugs but also to those of the narcotic antagonists, acetylsalicylic acid, and physostigmine.3. The effects of morphine and pentazocine were antagonized by naloxone but not by atropine, while the effects of physostigmine were antagonized by atropine but not by naloxone. Neither atropine nor naloxone antagonized the effect of acetylsalicylic acid.4. The results of the tolerance study suggest that there is a fundamental difference in the consequences of receptor interaction for the narcotic and the narcotic-antagonist analgesics. Morphine-tolerant mice exhibit cross-tolerance non-specifically. The selectivity of naloxone and atropine differentiates the narcotic and narcotic-analgesics from the other two agents used in this analgesic test.

Analgesics↗

Effects of narcotic analgesics and antagonists on the in vivo release of acetylcholine from the cerebral cortex of the cat.

1. In cats under light allobarbitone anaesthesia, the effects of intravenous injections of narcotic and non-narcotic analgesics, of a general depressant, and of narcotic antagonists were investigated on the spontaneous release of acetylcholine (ACh) from the surface of the sensorimotor cortex.2. The narcotic analgesics morphine (0.1, 1.0 and 5 mg/kg), meperidine (1.0 and 2.0 mg/kg), methadone (1.0 mg/kg) and codeine (5.0 and 10.0 mg/kg) greatly reduced ACh release.3. The non-narcotic analgesics pentazocine (1.0 and 2.0 mg/kg) and propoxyphene (5.0 and 10.0 mg/kg) as well as the depressant chlorpromazine (0.25, 0.5 and 1.0 mg/kg) also greatly reduced ACh release.4. Two of the three narcotic antagonists examined, levallorphan (0.1, 1.0 and 5 mg/kg) and nalorphine (1.0 mg/kg) had the property of reducing ACh release. They were thus partial agonists. With levallorphan the greatest reduction occurred with the smallest dose injected and the effect was regularly obtained, whereas with nalorphine a reduction was obtained in some experiments only. The third, naloxone, was a specific narcotic antagonist and did not reduce the ACh release in any dose (0.01, 0.1, 0.5 and 1.0 mg/kg) examined. In a dose of 1.0 mg/kg it actually produced a small increase in Ach release.5. Naloxone (0.1-1.0 mg/kg) restored the reduction in ACh release produced by the narcotic analgesics and by the partial agonist levallorphan. It partially restored the reduction produced by the non-narcotic analgesics and by nalorphine, but had no effect on the reduction produced by chlorpromazine.6. The relevance of these results with regard to analgesia and to the narcotic abstinence syndrome is discussed.

Acetylcholine↗

C-fragment of lipotropin--an endogenous potent analgesic peptide.

1 A series of peptides derived from porcine lipotropin was examined for analgesic and other morphine-like properties on infusion into the cannulated third ventricle of cats.2 Lipotropin (LPH 1-91) itself produced no analgesia or other morphine-like effects when infused in a dose of 150 mug.3 C-fragment (LPH 61-91) produced strong long-lasting analgesia when infused in a dose of 10 or 20 mug; on a molar basis the potency was between 90 and 180 times that of morphine. The following morphine-like effects were also produced: shivering leading to fever, vasodilatation of the pinnae, mydriasis, opening of the palpebral fissures, tachypnoea with bouts of panting, vocalization, hyperexcitability, restlessness and catalepsy. All the effects, including analgesia, were abolished by an intraperitoneal injection of naloxone (1 mg/kg).4 Hyperglycaemia, another central effect produced by morphine, was obtained with C-fragment infused in a dose of 60 mug.5 On intravenous injection, C-fragment produced analgesia with a dose of about 200 mug/kg. Administered by this route, C-fragment was again more potent than morphine.6 C'-fragment (LPH 61-87), LPH 61-78 and LPH 61-69, either had no analgesic effect or produced weak short-lasting analgesia when infused in doses up to 100 mug.7 Methionine enkephalin (LPH 61-65) either produced very weak short-lasting analgesia or had no analgesic effect when infused in doses of between 30 and 400 mug.8N-methyl methionine enkephalin amide in which both termini of methionine enkephalin were protected against degradation by exopeptidases produced long-lasting analgesia when infused in doses of 150 to 180 mug; its analgesic potency was approximately 100 times less than that of C-fragment. Blocking only one terminus of methionine enkephalin did not appear to endow the peptide with analgesic properties. The N-methyl pentapeptide amide produced other morphine-like effects of which the most striking was catalepsy. All the effects were abolished by intraperitoneal naloxone (1 mg/kg).

Analgesics↗

Comparison of perioperative analgesic protocols for dogs undergoing tibial plateau leveling osteotomy.

OBJECTIVE: To compare effects of 3 commonly used perioperative analgesic protocols (epidural injection, intra-articular injection, and intravenous [IV] injection) for management of postoperative pain in dogs after tibial plateau leveling osteotomy (TPLO). STUDY DESIGN: Prospective, randomized clinical trial. ANIMALS: Fifty-six healthy dogs with naturally occurring cranial cruciate ligament rupture. METHODS: Dogs were premedicated with IV hydromorphone and acepromazine and were randomly assigned to receive either E (preoperative epidural injection with morphine and bupivacaine), IA (pre- and postoperative intra-articular injections of bupivacaine), or C (neither epidural morphine and bupivacaine, nor intra-articular bupivacaine). All dogs were administered hydromorphone (0.05 mg/kg IV) at extubation and as needed to maintain comfort postoperatively. Patients were observed and monitored continuously for 24 hours and discomfort was assessed using visual analog pain scores (VASs), multifactorial pain scores (MPSs), and response to a pressure nociceptive threshold (PNT) measuring device. Time to 1st dose and the total doses of hydromorphone required to achieve adequate comfort for each dog were recorded. RESULTS: No differences in measured indices of postoperative pain were observed between dogs of each treatment group; VAS (P=.190), MPS (P=.371), and PNT (P=.160). Time to 1st analgesic intervention was longer for Group E compared with Group C (P=.005) and longer for Group IA compared with Group C (P=.032). Although time to 1st intervention between Groups E and IA were longer for Group E, differences were not significant. To provide an adequate level of comfort, more analgesic interventions were administered to dogs in Group C compared with dogs in group E (P=.015). On average, more hydromorphone was administered to Group C compared with Group IA (P=.072) and to Group IA compared with Group E (P=.168), but statistical significance was not reached for these data. CONCLUSIONS: In this study population, significant differences were seen in time to 1st hydromorphone dose between Groups E and IA compared with Group C. As well, more supplemental analgesia was administered to Group C compared with Group E to maintain the same level of postoperative comfort. Although differences between Groups E and IA tended to favor the epidural group, differences were minimal and not statistically significant. CLINICAL RELEVANCE: Our results suggest that regardless of analgesic protocol, measured indices of pain in dogs after TPLO can be minimized if dogs are continuously observed and appropriately supplemented with parenteral opioids. However, the frequency of postoperative opioid dosing can be minimized and may be a factor when contemplating supplementary use of epidural or intra-articular injections as part of a balanced analgesic approach.

Analgesia↗

The analgesic effect of buprenorphine, etorphine and pethidine in the pig: a randomized double blind cross-over study.

In order to find a suitable analgesic for the treatment of postoperative pain in pigs the analgesic effect of buprenorphine, etorphine and pethidine has been compared in 8 domestic pigs. For assessment of the analgesic action on thermal (hot plate) and two mechanical (cannulation of ear vein, needle prick) noxious stimuli have been employed. In a pilot experiment on 2 pigs in which methadone was included the maximal effective doses were estimated for each drug. Methadone was found unsuitable because of unacceptable side effects (respiratory dysfunction, hyperactivity) at effective dose levels. Next buprenorphine 120 micrograms/kg, etorphine 3 micrograms/kg and pethidine 20 mg/kg all given intramuscularly were compared in a randomized blind trial with a balanced cross-over design on 6 pigs. Etorphine proved to have the highest and pethidine the lowest maximal analgesic effect which was especially evident in the needle-prick test. Buprenorphine proved to have the longest duration of action in all three analgesic tests, in the hot plate test lasting between 7 and 24 hrs. Etorphine had a duration of 3 to 5 hrs whereas the effect of pethidine was short, only lasting about 2 hrs. Etorphine provides a complete analgesia but has a small safety margin for which reason it should be used with caution in the pig. The experimental results indicate that buprenorphine should be the first drug of choice in the treatment of pain after surgical intervention due to its long duration of action and lack of side effects.

Analgesia↗

Experimental human pain models: a review of standardised methods for preclinical testing of analgesics.

Treatment of pain is one of the major challenges in clinical medicine. However, it is often difficult to evaluate the effect of a treatment, as the many symptoms of the underlying diseases often confound this assessment. Furthermore, as the pain mechanisms in many diseases are poorly understood, the limited successful trial and error approach is most often used in the selection of analgesics. Hence, there is a need for new methods in the characterization and treatment of pain. Human experimental pain models offer the possibility to explore the pain system under controlled settings. The models can also be used to screen the analgesic profiles of drugs targeted to treat pain. This review gives a brief introduction to the methods used to evoke and assess pain in the skin, muscle and viscera. New methods using multimodal stimulation and activation of central pain mechanisms can to a higher degree mimic the clinical situation, and such methods are recommended in the future screening of analgesics. Examples of the use of experimental pain models in the testing of analgesics are given. With these models the therapeutic spectrum may be defined from a differentiated knowledge on the effect of drugs on the pain system. Such information may be used in the future guidelines for trials and clinical use of analgesics.

Analgesics↗

Multi-modal and tissue-differentiated experimental pain assessment: reproducibility of a new concept for assessment of analgesics.

Experimental pain models for assessment of analgesic effect needs to be reproducible, valid and responding in a uniform way to changes in pain level. The pain system differs in various tissue types and analgesics may have different effects in different tissues. This study assessed the reproducibility of an experimental model using mechanical, thermal and electrical stimulations. Pain was evoked in three tissues: Skin, muscle and viscera. Pain was evoked and assessed in 24 healthy volunteers. The experiment was repeated three times with 30 min. intervals and twice with a weekly interval. Systematic bias, intra-class correlation (ICC) and coefficient of variation (CV) and valid sample sizes for analgesic testing were assessed. The model proved to be feasible. Most tests were unbiased, showing stable means except for the mechanical and thermal stimulation in viscera, which showed decreasing pain thresholds when the tests were repeated with 30 min. intervals. Generally the pain tests showed relatively high CV (mean 71%, range 8-145%). The pain tests showed high ICC's (>0.80) when repeated on the same day. When the tests were repeated with an interval of one week, ICC was smaller (mean 0.79 range 0.49-0.96). This means that these tests are useful for analgesic testing recruiting useful sample sizes in a crossover (mean 31 range 2-84) and a parallel study (mean 59 range 3-164) design. Application of this experimental pain model in a cross-over study design with appropriate base-line recordings offers a unique opportunity of revealing analgesic effects on pain arising from different tissues.

Adult↗