Influence of a high-fat meal on the absorption of morphine from oral solutions.

The influence of a high-fat meal on blood morphine concentrations after the administration of a morphine solution (50 mg dose) was studied in 12 patients with chronic pain. The oral morphine dose was administered in a total volume of 200 ml to patients either immediately after food intake or while in the fasting state. There was a 34% increase in the area under the curve (AUC) when morphine was administered immediately after food when compared with the fasting state (p less than 0.02). However, there was no significant difference between the maximum blood morphine concentration (Cmax) or the time to maximum concentration (tmax) between the two treatment regimens. The shape of the blood morphine concentration-time curve was consistently altered in the fed patients compared with patients who were in the fasting state, inasmuch as the blood morphine concentrations were maintained at a higher level from 240 to 600 minutes after the dose when the morphine was administered with food (p less than 0.02). It is suggested that morphine concentrations are maintained at higher levels, possibly resulting in more prolonged pain relief, when morphine is administered with food compared with the same dose administered to patients who are in the fasting state.

Epidural mass associated with lack of efficacy of epidural morphine and undetectable CSF morphine concentrations.

A case is presented in which epidurally administered morphine failed to provide the expected extent and duration of pain relief. The patient had severe back pain in the upper lumbar and low thoracic regions and epigastric pain which was presumed to be caused by widespread metastatic deposits in the vertebral column from a prostatic carcinoma. The lack of clinical effect of epidural morphine was shown to be related to the unexpected presence of an epidural mass which was located below the dermatomal region for the patient's pain. Myelography and a CT scan indicated that the mass effectively compressed the subarachnoid space, thereby preventing the rostral spread of morphine in the cerebrospinal fluid (CSF) following lumbar epidural administration, resulting in inadequate pain relief.

Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury.

A prospective, longitudinal study of 100 people with traumatic spinal cord injury (SCI) was performed to determine the time of onset. prevalence and severity of different types of pain (musculoskeletal, visceral, neuropathic at level, neuropathic below level) at 2, 4, 8, 13 and 26 weeks following SCI. In addition, we sought to determine the relationship between physical factors such as level of lesion, completeness and clinical SCI syndrome and the presence of pain. At 6 months following SCI, 40% of people had musculoskeletal pain, none had visceral pain, 36% had neuropathic at level pain and 19% had neuropathic below level pain. When all types of pain were included, at 6 months following injury, 64% of people in the study had pain, and 21% of people had pain that was rated as severe. Those with neuropathic below level pain were most likely to report their pain as severe or excruciating. There was no relationship between the presence of pain overall and level or completeness of lesion, or type of injury. Significant differences were found, however, when specific types of pain were examined. Musculoskeletal pain was more common in people with thoracic level injuries. Neuropathic pain associated with allodynia was more common in people who had incomplete spinal cord lesions, cervical rather than thoracic spinal cord lesions, and central cord syndrome. Therefore, this study suggests that most people continue to experience pain 6 months following spinal cord injury and 21% of people continue to experience severe pain. While the presence or absence of pain overall does not appear to be related to physical factors following SCI, there does appear to be a relationship between physical factors and pain when the pain is classified into specific types.

Leakage of fluid administered epidurally to rats into subcutaneous tissue.

Epidural catheters were implanted in rats under halothane/nitrous oxide anaesthesia. Contrast medium (Iopamidol) was injected via the catheter under fluoroscopic control 24-48 h after implantation. In 15 of 20 rats contrast could be seen leaking out of the epidural space, usually after only 25 microliters was administered. Leakage was associated with diminished antinociceptive response to morphine administered via the catheter. Both leakage and decreased response to morphine could be largely prevented by applying a drop of Supa-Glue over the site of entry of the catheter to the epidural space at the time of catheter implantation. Investigators using epidurally cannulated rats should document that leakage does not occur or discard results from rats showing evidence of leakage.

Chronic pain in Australia: a prevalence study.

This study reports chronic pain prevalence in a randomly selected sample of the adult Australian population. Data were collected by Computer-Assisted Telephone Interview (CATI) using randomly generated telephone numbers and a two-stage stratified sample design. Chronic pain was defined as pain experienced every day for three months in the six months prior to interview. There were 17,543 completed interviews (response rate=70.8%). Chronic pain was reported by 17.1% of males and 20.0% of females. For males, prevalence peaked at 27.0% in the 65--69 year age group and for females, prevalence peaked at 31.0% in the oldest age group (80--84 years). Having chronic pain was significantly associated with older age, female gender, lower levels of completed education, and not having private health insurance; it was also strongly associated with receiving a disability benefit (adjusted OR=3.89, P<0.001) or unemployment benefit (adjusted OR=1.99, P<0.001); being unemployed for health reasons (adjusted OR=6.41, P<0.001); having poor self-rated health (adjusted OR=7.24, P<0.001); and high levels of psychological distress (adjusted OR=3.16, P<0.001). Eleven per cent of males and 13.5% of females in the survey reported some degree of interference with daily activities caused by their pain. Prevalence of interference was highest in the 55--59 year age group in both males (17.2%) and females (19.7%). Younger respondents with chronic pain were proportionately most likely to report interference due to pain, affecting 84.3% of females and 75.9% of males aged 20--24 years with chronic pain. Within the subgroup of respondents reporting chronic pain, the presence of interference with daily activities caused by pain was significantly associated with younger age; female gender; and not having private health insurance. There were strong associations between having interfering chronic pain and receiving disability benefits (adjusted OR=3.31, P<0.001) or being unemployed due to health reasons (adjusted OR=7.94, P<0.001, respectively). The results show that chronic pain impacts upon a large proportion of the adult Australian population, including the working age population, and is strongly associated with markers of social disadvantage.

Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations.

This study demonstrates that the exposure of phenobarbitone-treated rats to halothane at an oxygen concentration of either 10% or 14% results in marked decreases in cytochrome P-450 content and aminopyrine demethylase activity in animals sacrificed from 1 to 48 hr post-exposure. The alterations observed in the hepatic mixed function oxidase system were accompanied by increases in serum alanine aminotransferase (ALT), ornithine carbamyl transferase (OCT) and changes in liver pathology. However, the minor changes in cytochrome P-450 content and aminopyrine demethylase activity observed following exposure of enzyme-induced rats to halothane under normoxic conditions (i.e. 21% oxygen) were not of a sufficient magnitude to lead to hepatic cell necrosis. Halothane administration in the absence of phenobarbitone pretreatment (i.e. 21% oxygen) or during hypoxia alone (i.e. either 10% or 14% oxygen) did not result in any systematic changes in the parameters assayed. The results suggest that cytochrome P-450 may catalyse its own inactivation by virtue of greater free radical production under conditions which favour the non-oxygen dependent metabolism of halothane. The impairment in microsomal function as evidenced by decreases in cytochrome P-450 and aminopyrine demethylase activity are considered to occur as a primary consequence of the reductive metabolism of halothane. Data are presented which support the concept of the initiation of hepatic damage occurring during the period of anaesthesia with halothane.

Effect of subcutaneous administration of calcium channel blockers on nerve injury-induced hyperalgesia.

Recent studies suggest that calcium contributes to peripheral neural mechanisms of hyperalgesia associated with nerve damage. In this animal behavioural study, we examined further the contribution of calcium in neuropathic pain by testing whether subcutaneous administration of either a calcium chelating agent or voltage-dependent calcium channel blockers attenuate nerve injury-induced hyperalgesia to mechanical stimulation. Studies were carried out in animals with partially ligated sciatic nerves, an established animal model of neuropathic pain. The nociceptive flexion reflex was quantified using an Ugo Basile Analgesymeter. Partial nerve injury induced a significant decrease in mechanical threshold compared to the sham operated controls. Daily subcutaneous injections of the calcium chelating agent, Quin 2 (20 microgram/2.5 microliter), significantly attenuated the nerve injury-induced hyperalgesia. Similarly, SNX-111, a N-type channel blocker, also significantly attenuated the nerve injury-induced hyperalgesia. SNX-230, a P and/or Q-type channel blocker, and nifedipine, a L-type channel blocker, had no effect on the hyperalgesia to mechanical stimulation. In control experiments, SNX-111 had no effect on mechanical thresholds when administered subcutaneously in either the hindpaw of normal animals or the back of the neck in nerve injury animals. This study shows that neuropathic pain involves a local calcium-dependent mechanism in the receptive field of intact neurons of an injured nerve, since it can be alleviated by subcutaneous injections of either a calcium chelating agent or SNX-111, a N-type calcium channel blocker. These agents may be effective, peripherally acting therapeutic agents for neuropathic pain.

Celiac plexus block following high-dose opiates for chronic noncancer pain in a four-year-old child.

This is the first case report documenting the use of a neurolytic celiac plexus block for relieving chronic noncancer pain in a pediatric patient. The child was a 4-yr-old male with an unknown form of inflammatory bowel disease since 1 yr of age. Chronic abdominal pain became a problem at 3 yr of age, following multiple bowel resections; continuous intravenous narcotic administration was implemented for pain control. The patient's pain became refractory to high-dose morphine administration (maximum dose, 267 mg/kg/day, iv), and, for that reason, a CT-guided neurolytic celiac plexus block was performed. This procedure resulted in improved pain control along with a major reduction in narcotic use to 7 mg/kg/day of morphine.

Spinal pain mechanisms.

Pain is an extremely complex process that involves the interaction of an array of neurotransmitters and neuromodulators at all levels of the neuraxis. Identification of the receptors and processes that are involved in the transmission of pain at a spinal level has led to the use of new agents and new techniques in pain management. These include use of preemptive analgesia and use of techniques such as intrathecal drug administration and epidural spinal cord stimulation. This review presents some of the findings from basic research that have led to these developments, particularly those that relate to the changes that occur following inflammation and nerve injury.

Lack of secondary hyperalgesia and central sensitization in an acute sheep model.

BACKGROUND AND OBJECTIVES: We aimed to determine the following in an experimental acute pain model in sheep: (1) whether multimodal analgesia with intravenous fentanyl and ketorolac was more effective than fentanyl alone; (2) whether secondary hyperalgesia (central sensitization) occurred in adjacent (foreleg) dermatomes after thoracic surgery; (3) whether ketorolac used preemptively influenced the development of secondary hyperalgesia after surgery. METHODS: Changes in primary nociception were measured by increases to tolerated pressure, applied to the foreleg by a blunt pin, before foreleg withdrawal occurred. Changes to breath-to-breath interval and estimated end-tidal CO2 were used as indices of respiratory effects. Study 1 (n = 6) compared the paired responses to acute nociception after ketorolac (90 mg) or saline (control) pretreatment, followed by fentanyl (graded, 0 mg to 1.5 mg). Study 2 (n = 6) used a cross-over of ketorolac (90 mg) or saline (control) 24 hours and 1 hour, respectively, before a standardized thoracotomy incision, followed by antinociceptive testing with ketorolac (90 mg) and fentanyl (0.6 mg) daily over 4 days. RESULTS: In study 1, fentanyl produced naloxone-antagonizable antinociception and respiratory depression. Ketorolac did not affect fentanyl antinociception, except for prolonging antinociception at the highest dose; it did not affect the respiratory effects. In study 2, preemptive ketorolac had no effect on the postoperative antinociceptive or respiratory effects of fentanyl. The pharmacokinetics of fentanyl were unaltered by ketorolac. CONCLUSIONS: The results obtained in this acute pain model found no significant evidence of a fentanyl-ketorolac interaction, of central sensitization as shown by secondary hyperalgesia, or of a preemptive analgesic effect.

Glutamate and kynurenate in the rat central nervous system following treatments with tail ischaemia or diclofenac.

Kynurenate is an endogenous antagonist at the allosteric glycine site on the N-methyl-D-aspartate (NMDA) receptor, and may have a role in ameliorating nociceptive processes through modulation of NMDA receptor function. While antinociceptive effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are mediated peripherally and possibly centrally through inhibition of prostaglandin synthesis, there is also evidence for centrally mediated prostaglandin-independent antinociceptive effects that may result from increased central nervous system (CNS) concentrations of kynurenate. We have investigated the effects of the NSAID diclofenac, (40 mg kg(-1), s.c.; administered to rats 1 h before killing) or the exposure of rats to noxious stimulation (tail ischaemia for 20 min before killing), on the concentrations of glutamate and kynurenate in discrete CNS regions. Regional CNS tissue concentrations of diclofenac were between 3.0-3.8 nmolg(-1). The corresponding regional glutamate concentrations ranged between 4.8-10.6 micromol g(-1), and were significantly lower in the ischaemia group when compared with both control (15%, P < 0.05) and diclofenac-treated (19%, P < 0.002) groups. Kynurenate concentrations in these CNS regions ranged between 3.3-45.8 pmol g(-1). Pairwise comparisons between the control and diclofenac-treated groups found significant increases in kynurenate concentrations in the diencephalon and lumbo-sacral regions of the CNS (P = 0.05). Noxious stimulation from tail ischaemia appeared to be associated with increased release of glutamate. Additionally, NSAIDs appeared to increase kynurenate concentrations in the spinal cord and diencephalon. Antagonism by kynurenate of glutamate effects at NMDA receptors may contribute to the antinociceptive effects of NSAIDs.

Analysis of 50 patients with atypical odontalgia. A preliminary report on pharmacological procedures for diagnosis and treatment.

Atypical odontalgia is a distressing and unusual chronic orofacial pain condition. It is often difficult to diagnose because it is associated with a lack of clinical and radiographic abnormalities. The condition is poorly understood on a pathophysiological basis, and patients often undergo repetitive and unnecessary dental procedures in attempts to alleviate pain. In this study, 50 patients diagnosed with odontalgia were evaluated by pharmacological procedures, including topical anesthetic application and phentolamine infusion. Results of these pharmacological procedures suggest that atypical odontalgia is a neuropathic pain of the oral cavity that may have a component of sympathetically maintained pain. Therapeutic trials of topical capsaicin were carried out to assess its efficacy for pain reduction. Topical capsaicin was effective in most patients.

Pain description and severity of chronic orofacial pain conditions.

A multidisciplinary pain centre study of 120 consecutive chronic orofacial pain patients assessed pain description and intensity ratings, gender differences, prevalence of concurrent conditions, and interinstrument relationships of the McGill Pain Questionnaire and visual analogue scale. Pain words chosen by patients to describe conditions were predominantly sensory words, and patients with concurrent conditions often listed words indicating a substantial affective component. Results showed pain intensity ratings of chronic orofacial pain conditions have similar or higher pain ratings when compared with other medical chronic pain conditions such as back pain, cancer pain and arthritis. There was a significantly higher female: male ratio (88:32) with gender playing an important but poorly understood causal role. The most frequent condition diagnosed was atypical facial pain (n = 40), followed by temporomandibular disorder (n = 32), atypical odontalgia (n = 29) and pathology of the orofacial region (n = 19). Temporomandibular disorder was present in 75 of the 120 subjects, as the sole pain complaint (n = 32) or as an associated secondary condition (n = 43), indicating concurrent pain conditions exist and may be related. There were significantly higher total pain scores of the McGill Pain Questionnaire in patients with multiple conditions compared with patients with a single condition. The visual analogue scale showed a significant correlation to the number of words chosen index of the McGill Pain Questionnaire for orofacial pain.

Neuropathic orofacial pain. Part 2-Diagnostic procedures, treatment guidelines and case reports.

Neuropathic orofacial pain can be difficult to diagnose because of the lack of clinical and radiographic abnormalities. Further difficulties arise if the patient exhibits significant distress and is a poor historian regarding previous diagnostic tests and treatments, such as somatosensory local anaesthetic blockade. Valuable information can be obtained by utilising the McGill Pain Questionnaire that allows the patient to choose words that describe the qualities of his/her pain in a number of important dimensions (sensory and effective). Basal pain intensity should be measured with the visual analogue scale, a simple instrument that can evaluate the efficacy of subsequent treatments. The dentist or endodontist can employ sequential analgesic blockade with topical anaesthetics and perineural administration of plain local anaesthetic to ascertain sites of neuropathology in the PNS. These can be performed in the dental chair and in a patient blinded manner. Other, more specific, tests necessitate referral to a specialist anaesthetist at a multidisciplinary pain clinic. These tests include placebo controlled lignocaine infusions for assessing neuropathic pain, and placebo controlled phentolamine infusions for sympathetically maintained pain. The treatment/management of neuropathic pain is multidisciplinary. Medication rationalisation utilises first-line antineuropathic drugs including tricyclic antidepressants such as amitriptyline and nortriptyline, and possibly an anticonvulsant such as carbamazepine, sodium valproate, or gabapentin if there are sharp, shooting qualities to the pain. Mexiletine, an antiarrhythmic agent and lignocaine analogue, may be considered following a positive patient response to a lignocaine infusion. All drugs need to be titrated to achieve maximum therapeutic effect and minimum side effects. Topical applications of capsaicin to the gingivae and oral mucosa are a simple and effective treatment in two out of three patients suffering from neuropathic orofacial pain. Temporomandibular disorder is present in two thirds of patients and should be assessed and treated with physiotherapy and where appropriate, occlusal splint therapy. Attention to the patient's psychological status is crucial and requires the skill of a clinical psychologist and/or psychiatrist with pain clinic experience. Psychological variables include distress, depression, expectations of treatment, motivation to improve, and background environmental factors. Unnecessary dental treatment to "remove the pain" with dental extractions is contraindicated and aggravates neuropathic orofacial pain.

Neuropathic orofacial pain part 1--prevalence and pathophysiology.

Neuropathic pain is defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system". Neuropathic orofacial pain has previously been known as "atypical odontalgia" (AO) and "phantom tooth pain". The patient afflicted with neuropathic oral/orofacial pain may present to the dentist with a persistent, severe pain, yet there are no clearly identifiable clinical or radiographic abnormalities. Accordingly, multiple endodontic procedures may be instigated to remove the likely anatomical source of the pain, yet the pain persists. There have been few studies and limited patient numbers investigating the condition. Two retrospective studies revealed the incidence of persistent pain following endodontic treatment to be 3-6% and 5% of patients; one author with wide experience in assessing the condition estimated its prevalence at 125,000 individuals in the USA alone. In one study, 50% of neuropathic orofacial pain patients reported persistent pain specifically following endodontic treatment. Patients predisposed to the condition may include those suffering from recurrent cluster or migraine headaches. Neuropathic pain states include postherpetic neuralgia (shingles) and phantom limb/stump pain. The aberrant developmental neurobiology leading to this pain state is complex. Neuropathic pain serves no protective function, in contrast to physiological pain that warns of noxious stimuli likely to result in tissue damage. The relevant clinical features of neuropathic pain include: (i) precipitating factors such as trauma or disease (infection), and often a delay in onset after initial injury (days-months), (ii) typical complaints such as dysaesthesias (abnormal unpleasant sensations), pain that may include burning, and paroxysmal, lancinating or sharp qualities, and pain in an area of sensory deficit, (iii) on physical examination there may be hyperalgesia, allodynia and sympathetic hyperfunction, and (iv) the pathophysiology includes deafferentation, nerve sprouting, neuroma formation and sympathetic efferent activity.

Neural blockade in chronic pain.

Neuroblockade techniques can serve many functions in the management of the chronic pain patient. These various functions are discussed and a brief insight given for their use in specific pain syndromes. A run-down of the type of blocks useful in the management of cancer pain is also given.

Failed back surgery syndrome.

Patient selection for repeated spinal surgery is not uniform and must be further refined. A multidisciplinary approach with careful evaluation of physical, psychological and environmental factors is ideal. Improved imaging should delineate disorders more clearly, and advances in surgical technique may improve outcome. It is likely, however, that a number of patients will continue to require long-term pain management.

Monitoring--the anaesthetist's view.

There is large variability in the pharmacokinetics and pharmacodynamics of sedative drugs in patients thus, a standard dose of sedative may produce undersedation in certain patients and substantial oversedation, resulting in anaesthesia, in others. Those who administer sedatives should, therefore, have the knowledge, skill, and equipment (including monitoring devices) to enable them to deal with an oversedated patient. Certain patients are at an increased risk of complications owing to sedative administration. Preoperative assessment of patients will enable the endoscopist to determine when and how to monitor the patient. If continuous monitoring is used, early detection of any potentially dangerous pathophysiology is more likely, and thus, the risk of cardiorespiratory arrest is minimized. Clinical observation is essential but can be supplemented by some extremely reliable and effective devices. Of these, the most important and relevant for monitoring during endoscopy is finger pulse oximetry. This technique is easy to use, does not interfere with the endoscopy procedure, enables continuous monitoring, and is extremely versatile. Pulse oximetry can also alert staff to cardiorespiratory problems.