[Oral transmucosal fentanyl citrate (OTFC) in the treatment of breakthrough pain]. / Oral transmukosal fentanylcitrat (OTFC) til behandling af gennembrudssmerter.

Breakthrough pain in patients receiving opioids for pain relief is traditionally treated with opioids given orally. This, however, implies a long time to clinical effect and a long duration of action resulting in difficult titration. It is possible to give fentanyl orally for transmucosal absorption (OTFC) with a new formulation using a stick with a specially designed tablet that can be rubbed against the mouth mucosa. This gives a short time to effect and with a short duration of action. Clinical studies have shown that patient tolerance of OTFC is high and the analgesic effect is comparable to that of intravenous fentanyl, without the need for an i.v. line. Clinical indication will be breakthrough pain in patients receiving opioids for baseline pain medication.

Pain and pain treatment in AIDS patients: a longitudinal study.

To determine the prevalence, incidence, and characteristics of pain connected with AIDS, 95 AIDS patients were enrolled in a prospective longitudinal study and interviewed every six months during a 2-year period or until death. The overall incidence of pain was 88%, and 69% of the patients suffered from constant pain interfering with daily living to a degree described as moderate or severe. The most common pain localizations were: extremities (32%), head (24%), upper gastrointestinal tract (23%) and lower gastrointestinal tract (22%). Pain conditions were connected to various opportunistic infections, Kaposi's sarcoma, or lymphoma. Pain in the extremities was predominantly of neuropathic origin (21%). The number of pain localizations increased significantly as death approached (0.8 +/- 1. 0 vs. 1.4 +/- 0.8, p = 0.03). The survival rate for patients without pain at entry was significantly higher than the survival rate of patients in pain, probably related to differences in the duration of AIDS at the time of inclusion. Sustained-release morphine preparations were prescribed in 29% of the patients. Of 39 patients (41%) who died in the department, 7 patients were prescribed continuous intravenous morphine infusion for pain treatment in the terminal phase and 20 patients received short-acting opioids. According to the Pain Management Index (PMI), the patients were insufficiently treated at the beginning of the study. Although the PMI improved significantly during the observation period, the patients felt that pain was not taken seriously by the physicians. However, the patients were convinced that treatment was optimal and, therefore, only 9% of the patients were dissatisfied. Patients were reluctant to take analgesics, primarily because of fear of addiction.

The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans.

BACKGROUND: The (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity and is involved in the occurrence of secondary hyperalgesia. Ketamine is an NMDA-receptor antagonist and has proven effective in alleviating secondary hyperalgesia in humans. Although it is disputed, the actions of ketamine have been ascribed not only to NMDA receptor antagonism, but also to opioid receptor agonism. A study therefore was designed in which the abolishment of a previously demonstrated effect of ketamine on secondary hyperalgesia was sought by pretreatment with naloxone. METHODS: Twenty-five volunteers were subjected to three treatment regimens. A standardized first-degree burn injury was induced. On appearance of primary and secondary hyperalgesia, one of the following infusion schemes was applied in a randomized, double-blind, cross-over fashion: (1) infusion of naloxone (0.8 mg/15 min followed by 0.4 mg/h), succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); (2) infusion of placebo, succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); and (3) infusion of placebo, succeeded by infusion of placebo. Heat-pain detection thresholds, magnitude of secondary hyperalgesia around the burn injury, and side effects were determined. RESULTS: Ketamine reduced secondary hyperalgesia. Naloxone did not affect the action of ketamine. The magnitudes of side effects were equal if the subjects received ketamine, regardless of preceding infusion of naloxone. CONCLUSIONS: In this experimental setting, opioid receptor blockade does not inhibit ketamine-induced reductions of secondary hyperalgesia.

Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord.

The enantiomers of the potent non-competitive NMDA receptor antagonist ketamine and its major metabolite, norketamine were evaluated as NMDA receptor antagonists using the rat cortical wedge preparation and the neonatal rat spinal cord preparation, respectively, for electrophysiological studies and [3H](RS)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine ([3H]MK801) in homogenate binding experiments. In agreement with earlier studies (S)-ketamine (Ki 0.3 microM) was found to possess a 5 times higher affinity for the NMDA receptor complex than (R)-ketamine (Ki 1.4 microM). (S)-Norketamine (Ki 1.7 microM) had approximately an 8 times higher affinity than (R)-norketamine (Ki 13 microM) in the inhibition of [3H]MK-801 binding. All compounds inhibited responses to NMDA in the rat cortical wedge preparation and the hemisected neonatal rat spinal cord, being approximately four times more potent in the cortex than in the spinal cord except for (R)-norketamine being only twice as potent. In light of the clinically obtained concentrations of norketamine after oral administration of ketamine, these data strongly suggest that (S)-norketamine may contribute significantly to the clinical activity of (S)-ketamine, especially when given orally.

Segmental effects on motor function following different intrathecal receptor agonists and antagonists in rabbits.

BACKGROUND: The occurrence of motor impairment after intrathecal drug administration is infrequently reported in the literature and the methods of determining motor function vary. METHODS: Motor function was examined in rabbits after a wide dose range of a variety of intrathecally administered opioid agonists, alpha-adrenergic agonists, non-competitive NMDA antagonists, a benzodiazepine agonist, a sigma agonist, paracetamol, isotonic and acidified saline. The opioids, sigma agonist and NMDA antagonists were additionally examined following pretreatment with naloxone. The opioid antagonists naltrindole and MR2266 (delta- and kappa-opioid receptor antagonists, respectively) were administered before the delta agonist and the kappa agonist. The alpha 2-adrenergic antagonist yohimbine was given before administration of dexmedetomidine and xylazine. Motor function was evaluated by a five-point scale of motor impairment ranging from normal function to total paralysis of the hindlegs. RESULTS: DPDPE (delta agonist), paracetamol, naloxone, naltrindole, yohimbine, isotonic and acidified saline did not affect motor function. MR2266 produced minor motor impairment. The alpha-adrenergic agonist dexmedetomidine reduced motor function slightly and dose independently. The remaining compounds affected motor function in a dose-dependent fashion. High doses of morphine produced hypersensitivity and myoclonus. An irreversible paralysis of the hindlegs was observed following intrathecal administration of the sigma agonist SKF10047 in high doses. Naloxone and MR2266 attenuated the effects of U50488H (kappa agonist). CONCLUSION: The present results reveal a dose-dependent reduction in motor function after intrathecal administration of some of the investigated compounds. The mechanisms behind these effects appear to be multifactorial.

[Pain and treatment of pain in patients with AIDS]. / Smerter og smertebehandling hos AIDS-patienter.

Published articles report that 50-97% of patients with AIDS experience pain. The aim of the study was to determine the incidence and characteristics of pain connected with AIDS, to register pain treatment and patients' evaluation of such treatment. Ninety-five patients with AIDS underwent a semistructured interview. The overall incidence of AIDS-related pain was found to be 74%. Fifty-two percent of the patients experienced pain every day or constantly to a degree described as "some or severe". Thirty-one percent of the patients had a pain duration of more than three months and 25% of the patients were never free from pain. Eleven percent received medical pain treatment on a steady hourly basis. Despite these results, the majority of the patients were satisfied with the treatment and only three percent stated that they were not satisfied. It is concluded that patients with AIDS have a higher incidence of pain, which appears to be undertreated. The reason for this undertreatment is multifactorial. The patients appear to be very reluctant to receive medical pain treatment.

Tonic endogenous opioid inhibition of visceral noxious information in rabbits.

BACKGROUND & AIMS: A tonic intrinsic spinal inhibitory system on spinal motor reflexes in rabbits has been shown earlier. The aim of this study was to examine the effects of different opioid antagonists against visceral noxious stimulation in awake rabbits. METHODS: The opioid receptor antagonists examined were naloxone (nonselective), MR2266 (kappa), and naltrindole (delta). The effects on the visceromotor response thresholds induced by colorectal distention in rabbits were determined after intrathecal and intramuscular administration of the antagonists. RESULTS: Intrathecal naloxone resulted in a dose-dependent decrease of visceromotor response thresholds. The selective antagonists MR2266 and naltrindole had no significant effects. In the presence of MR2266, intrathecal naloxone reduced thresholds to the same degree as when given alone. Analysis of the data from all rabbits showed a statistically significant reduction in visceromotor response thresholds after intrathecal naloxone compared with intramuscular administration. CONCLUSIONS: In rabbits, tonic active intrinsic spinal and supraspinal endogenous opioids modulate visceral noxious information. This inhibition is exerted at the mu opioid receptor.

The effect of intrathecal opioid-receptor agonists on visceral noxious stimulation in rabbits.

BACKGROUND & AIMS: Conflicting results have been published concerning the effects of different opioid-receptor agonists against visceral noxious stimulation. The introduction of colorectal distention facilitates research in this field. The aim of this study was to examine intrathecally administered opioid agonists against colorectal distention in conscious rabbits. METHODS: Rabbits were equipped with a subcutaneous intrathecal injection system. Colorectal distention was induced by inflation of a balloon inserted into the descending colon. The test parameter was the pressure eliciting a characteristic visceromotor response. Examinations were performed before and after administration of the following drugs: morphine, U50488H, [D-Pen2, D-Pen5]enkephalin (DPDPE), naloxone, MR2266, naltrindole, saline, and acidified saline. RESULTS: The visceromotor response to colorectal distention was inhibited in a dose-dependent fashion by intrathecal opioids acting as agonists at all three types of opioid receptors. Morphine was antagonized more effectively by intrathecal than intramuscular naloxone. U50488H and DPDPE were equally antagonized by the specific antagonists MR2266 and naltrindole. Electrical thresholds in the lumbar region were increased, although they remained unaltered in the cervical region after administration of all three agonists. CONCLUSIONS: Intrathecal administration of different opioid agonists produces a dose-dependent spinal effect. The rank order of potencies in this model is DPDPE > U50488H > morphine > saline = 0.

[Ketamine in the management of intractable phantom pain]. / Ketamin til behandling af svaert behandlelige fantomsmerter.

A case of phantom limb pain, which had not successfully responded to a long list of medical therapy or neurosurgery, is presented. After oral ketamine treatment was instituted the patient became free of pain. A possible mode of action is described.

Legal opioid consumption in Denmark 1981-1993.

According to the World Health Organisation, a country's morphine consumption is an important indicator of progress in cancer pain relief. Due to its very high opioid consumption, Denmark is often pointed out as a country worthy of imitation. The aim of the present study was to analyse Danish opioid consumption in order to elucidate the usage pattern and to identify the consumers. Total opioid consumption increased 353% from 1981 to 1993, exceeding 1.45 million defined daily doses per million inhabitants in 1993. Morphine accounted for 39%, methadone 22%, ketobemidone 21% and buprenorphine for 14% of the consumption use. The consumption of long acting opioids (sustained release morphine, methadone, buprenorphine) and short acting opioids (others) increased by 1427% and 105%, respectively. Analysis of a sample of 1854 prescriptions for opioids revealed that less than 10% of the prescriptions were issued for cancer pain conditions. It is concluded: that if other countries consider Denmark as worthy of imitation in opioid treatment for cancer pain, attention should be paid to the pattern of the Danish opioid consumption, which is outstanding with respect to quantity but the quality may be questionable.

Histopathology after repeated intrathecal injections of preservative-free ketamine in the rabbit: a light and electron microscopic examination.

Epidural and spinal administration of ketamine has been used in humans. Single-dose studies have shown that preservative-free ketamine lacks neurotoxic effects, but there are no studies after repeated administrations. The aim of this study was to examine the effects of daily administration of preservative-free ketamine. Fourteen New Zealand albino rabbits were assigned to two groups receiving either intrathecal preservative-free ketamine 5 mg, 0.5 mL 1% solution (eight rabbits) or saline 0.5 mL (six rabbits) once a day for 14 consecutive days. The rabbits had a total subcutaneous implanted intrathecal catheter, which was introduced during general anesthesia. On Day 15 the rabbits were anesthetized and in vivo fixated by transcardial perfusion with Tyrode's solution followed by a mixture of 2% glutaraldehyde and 1% formaldehyde in a 0.1 mol/L phosphate buffer. A segment 5 cm on each side of the catheter tip was removed and kept in a cold solution of the fixative. Light microscopic, electron microscopic, and morphometric examinations showed no differences between the spinal cords from the rabbits injected with ketamine versus saline. Intrathecal ketamine produced motor impairment for a period of 15 min. We conclude that repeated intrathecal administration of preservative-free ketamine confirms the lack of neurotoxicity from single-dose studies.

[Opioid analgesics in the treatment of non-malignant chronic pain]. / Opioide analgetika i behandlingen af kroniske smerter af ikkecanceroprindelse.

Opioid sensitivity, residual pain, development of tolerance, physical and psychological dependence are described and discussed in relation to long-term opioid therapy. Based on this, guidelines for long-term opioid administration are established for chronic pain conditions of non-cancer origin. The indication must be well-considered--a life-long treatment may be instituted. Prior to final initiation of the treatment, a testing of the selected drug and method of administration should be performed. Due to the compliance-reasons, only long acting opioids should be used (controlled release morphine preparations, methadone, buprenorphine) and the route of administration should always be oral. The treatment must be individualised, covering 24 hours a day. The single dosages should be identical and administered with identical time intervals, which are determined by the duration of action of the drug in use. P.r.n.-administration should not be allowed. Only one physician should be responsible for the treatment and for the prescription of the opioid analgesic drugs.