Patient's and health care provider's perspectives on music therapy in palliative care - an integrative review.

BACKGROUND: The use of music as therapy in multidisciplinary end-of-life care dates back to the 1970s and nowadays music therapy (MT) is one of the most frequently used complementary therapy in in-patient palliative care in the US. However existing research investigated music therapy's potential impact mainly from one perspective, referring to either a quantitative or qualitative paradigm. The aim of this review is to provide an overview of the users' and providers' perspectives on music therapy in palliative care within one research article. METHODS: A systematic literature search was conducted using several databases supplemented with a hand-search of journals between November 1978 and December 2016. Inclusion criteria were: Music therapy with adults in palliative care conducted by a certified music therapist. Both quantitative and qualitative studies in English, German or a Scandinavian language published in peer reviewed journals were included. We aimed to identify and discuss the perspectives of both patients and health care providers on music therapy's impact in palliative care to forward a comprehensive understanding of it's effectiveness, benefits and limitations. We investigated themes mentioned by patients within qualitative studies, as well as commonly chosen outcome measures in quantitative research. A qualitative approach utilizing inductive content analysis was carried out to analyze and categorize the data. RESULTS: Twelve articles, reporting on nine quantitative and three qualitative research studies were included. Seven out of the nine quantitative studies investigated pain as an outcome. All of the included quantitative studies reported positive effects of the music therapy. Patients themselves associated MT with the expression of positive as well as challenging emotions and increased well-being. An overarching theme in both types of research is a psycho-physiological change through music therapy. CONCLUSIONS: Both quantitative as well as qualitative research showed positive changes in psycho-physiological well-being. The integration of the users´ and providers´ perspectives within future research applicable for example in mixed-methods designs is recommended.

Efficacy and side effects of intravenous remifentanil patient-controlled analgesia used in a stepwise approach for labour: an observational study.

BACKGROUND: Remifentanil has a suitable pharmacological profile for labour analgesia. In this prospective, observational study, intravenous patient-controlled analgesia with remifentanil, using stepwise bolus doses without background infusion, was examined during the first and second stages of labour. Outcomes were pain reduction, maternal satisfaction, maternal and neonatal side effects and remifentanil metabolism in the neonate. METHODS: Parturients with normal term singleton pregnancies were recruited. The initial remifentanil bolus dose was 0.15 µg/kg, increasing in steps of 0.15 µg/kg, with a 2-min lock-out. Pain scores using a 100 mm visual analogue scale, systolic and diastolic blood pressures, respiratory rate and maternal sedation were recorded every 15 min. Maternal oxygen saturation and heart rate were monitored continuously. Neonatal data included Apgar scores, clinical examination, naloxone use, resuscitation, umbilical cord blood gases and remifentanil concentrations. RESULTS: Forty-one parturients were enrolled. Pain scores were significantly reduced in the first 3 h of patient-controlled analgesia use compared to baseline, and at the end of the first and second stages of labour (P<0.05). Maximal pain reduction was 60% (P<0.01). One patient had inadequate pain relief and converted to epidural analgesia. The mean highest dose of remifentanil was 0.7 µg/kg [range 0.3-1.05]. Ninety-three percent of patients were satisfied with their analgesia. The lowest oxygen saturation was 91% and the lowest respiratory rate was 9 breaths/min. Eleven parturients (27%) received supplemental oxygen due to oxygen saturations <92%. Maternal sedation was moderate, and neonatal data reassuring. CONCLUSIONS: Remifentanil intravenous patient-controlled analgesia provides adequate pain relief and high maternal satisfaction during the first and second stages of labour. Maternal sedation and respiratory depression may occur, but no serious neonatal side effects were recorded. Careful monitoring is mandatory.

How to switch from morphine or oxycodone to methadone in cancer patients? a randomised clinical phase II trial.

AIM: Opioid switching is a treatment strategy in cancer patients with unacceptable pain and/or adverse effects (AEs). We investigated whether patients switched to methadone by the stop and go (SAG) strategy have lower pain intensity (PI) than the patients switched over three days (3DS), and whether the SAG strategy is as safe as the 3DS strategy. METHODS: In this prospective, open, parallel-group, multicentre study, 42 cancer patients on morphine or oxycodone were randomised to the SAG or 3DS switching-strategy to methadone. The methadone dose was calculated using a dose-dependent ratio. PI, AEs and serious adverse events (SAEs) were recorded daily for 14 days. Primary outcome was average PI day 3. Secondary outcomes were PI now and AEs day 3 and 14 and number of SAEs. RESULTS: Twenty one patients were randomised to each group, 16 (SAG) and 19 (3DS) patients received methadone. The mean preswitch morphine doses were 900 mg/day in SAG and 1330 mg/day in 3DS. No differences between groups were found in mean average PI day 3 (mean difference 0.5 (CI -1.2-2.2); SAG 4.1 (CI 2.3-5.9) and 3DS 3.6 (CI 2.9-4.3) or in PI now. The SAG group had more dropouts and three SAEs (two deaths and one severe sedation). No SAEs were observed in the 3DS group. CONCLUSION: The SAG patients reported a trend of more pain, had significantly more dropouts and three SAEs, which indicate that the SAG strategy should not replace the 3DS when switching from high doses of morphine or oxycodone to methadone.

Analgesia for labour: a survey of Norwegian practice - with a focus on parenteral opioids.

BACKGROUND: During the last two decades, epidural analgesia has become 'a gold standard' for labour pain in most Western countries. Newer short-acting opioids given systemically represent an alternative for adequate pain relief without using regional techniques. With this survey, we wish to explore how Norwegian hospitals practice labour analgesia, especially their use of systemic opioids. METHODS: A questionnaire was sent to the head of all 46 registered Norwegian labour units in 2005. The questionnaire focused on epidural and the use of systemic opioids. In 2008, the same questionnaire was sent to the 19 largest units reporting >1000 births a year, seeking updated information. RESULTS: Forty-three of the 46 original questionnaires were returned. An epidural frequency of 25.9% was registered. For epidural treatment, bupivacaine was the preferred local anaesthetic, while sufentanil was the opioid of choice for the majority of units. Pethidine was the most commonly used opioid for systemic administration (77%). All units reported nurse administration of systemic opioids. The intramuscular route was most commonly used, either alone (58%) or in combination with an intravenous (i.v.) administration (34%). Only one unit used i.v. fentanyl. There were only minor changes with the repeated survey, except for one large unit, which reported over a 50% increase in the epidural frequency. CONCLUSION: In Norway, the frequency of epidural for labour analgesia is still relatively low, but seems to be increasing. Systemic opioids are often used instead of or as a supplement. Clinical practice seems to be conservative, and newer short-acting opioids are seldom used systemically.

[Recurrent abdominal pain caused by acute intermittent porphyria]. / Residiverende magesmerter forårsaket av akutt intermitterende porfyri.

BACKGROUND: Acute intermittent porphyria is an inherited metabolic disorder which may remain undiagnosed throughout life unless appropriate biochemical analysis is being performed during an acute attack. MATERIALS, METHOD AND RESULTS: We describe a 26-year-old woman who had been suffering from recurrent abdominal pain for many years. She had been hospitalized several times; her appendix had been removed, and three diagnostic laparoscopies and several gynaecological procedures had not revealed the cause. During an intractable and increasing abdominal pain episode, porphyrins were detected in her urine. Her pain was then treated effectively with a combination of morphine, glucose and haem-arginat infusion. INTERPRETATION: In a patient suffering from repeated episodes of unexplainable abdominal colic, paresis or psychic symptoms, acute intermittent porphyria should be considered as a diagnosis.

Spinal cord transection--no loss of distal ventral horn neurons. Modern stereological techniques reveal no transneuronal changes in the ventral horns of the mouse lumbar spinal cord after thoracic cord transection.

Anterograde transneuronal degeneration is caused by the loss of afferent input to the nerve cells and may occur in a number of neuronal systems. Transection of the adult spinal cord, causing anterograde transneuronal degeneration in ventral horn neurons, distal to the lesion, has been reported by some authors, while others contend that no such changes take place. The present study was undertaken in order to investigate whether transection of adult mouse thoracic spinal cord induces neuronal death in the ventral horns distal to the lesion. By means of modern stereological techniques such as the optical dissector, the total number of cells in the lumbar ventral horns was estimated 7 weeks after transection. The mean numbers of neurons and glial and endothelial cells were 82,000 versus 89,000, 259,000 versus 301,000, and 129,000 versus 144,000 in the transected (n = 6) and sham-operated animals (n = 5), respectively. These differences were not statistically significant. Furthermore, neuronal soma volume was estimated by another stereological method, the vertical rotator. Mean neuronal soma volume was not significantly different between transected (2762 microns 3) and sham-operated (2617 microns 3) mice. Although no reduction in cell number or neuronal soma volume was observed, the mean volume of the ventral horns in the lumbar segments was significantly less in transected than in sham-operated animals, 2.49 mm3 versus 3.05 mm3 (P < 0.05). In conclusion, the transection of adult mouse thoracic spinal cord does not induce neuronal degeneration in the lumbar ventral horns.

Haemodynamic effects of high-dose vecuronium compared with pancuronium in beta-blocked patients with coronary artery disease during fentanyl-diazepam-nitrous oxide anaesthesia.

BACKGROUND: Different combinations of neuromuscular blockers and opioids have been used in patients with angina pectoris to provide cardiovascular stability and reduce risk of myocardial ischaemia during anaesthesia. METHODS: We have compared the haemodynamic effects of high-dose vecuronium (0.3 mg kg-1) with those of a standard dose of pancuronium (0.1 mg kg-1) in patients scheduled for coronary artery bypass grafting during fentanyl-diazepam-nitrous oxide anaesthesia. All patients were receiving beta-adrenergic blocking agents. The given doses of vecuronium and pancuronium are equieffective with respect to duration of neuromuscular blockade. RESULTS: During a 25-min experimental period following the administration of the randomly selected drug, no significant changes in the haemodynamic parameters were observed in the vecuronium group. The administration of pancuronium, however, resulted in a significant mean increase in heart rate (20%), rate-pressure product (23%) and cardiac index (21%). Following endotracheal intubation in the pancuronium group, we observed an additional significant increase in mean arterial pressure and rate-pressure product. CONCLUSION: High-dose administration of vecuronium has minimal haemodynamic effects and may thus offer a better alternative than pancuronium for long-lasting neuromuscular blockade in patients with coronary artery disease during fentanyl-diazepam-nitrous oxide anaesthesia.

Solid-state stereochemistry and activity of 3-methylnefopam diastereomers: manipulation of eight-membered ring conformations in analogues of the non-narcotic analgesic drug.

The solid-state structures of (+/-)-(1R,3S,5S)/(1S,3R,5R)- and (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-methylnefopam hydrochloride, epimeric 3-methyl derivatives of the non-narcotic analgesic drug, were determined by single-crystal X-ray diffraction analyses. (+/-)-(1R,3S,5S)/(1S,3R,5S)-3-Methylnefopam hydrochloride gave crystals belonging to the monoclinic space group P2(1)/c, and at ambient temperature, a = 7.993(2), b = 34.376(4), c = 11.785(2) A, beta = 93.06 degrees, V = 3234(2) A3, Z = 8, R(F = 0.070, and Rw(F) = 0.053. (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-Methylnefopam hydrochloride gave chiral crystals belonging to the orthorhombic space group P2(1)2(1)2(1), and at 92 K, a = 9.261(2), b = 10.280(2), c = 16.668(4) A, V = 1587(1) A3, Z = 4, R(F) = 0.034, and Rw(F) = 0.035. The two molecules in the asymmetric unit of the (1R,3S,5S)/(1S,3R,5R)-racemic modification had twist-chair-(flattened chair) [TCfC] conformational geometries for the eight-membered ring. Both molecules are virtually identical as shown by a root mean squares fit of 0.077 A in the superimposition of all nonhydrogen atoms in both molecules. The (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-epimers were found in the same boat-(flattened chair) [BfC] conformation previously noted for crystalline nefopam hydrochloride. The TCfC and BfC eight-membered ring conformations of the two 3-methylnefopam diastereomers differ in the -N+H(CH3)CH2CH-fragment chair or boat arrangement vis-a-vis the adjacent flattened region. In both 3-methyl diastereomers, the C(3)-methyl group was disposed in an equatorial orientation, the phenyl group resided in an exo-position, and the -OCH(Ph)-o-C6H4- fragment occupied the flattened region of the eight-membered ring.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and long term effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in tests of nociception in mice.

Acute and long term changes in nociception after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 80 mg/kg (four injections of 20 mg/kg given at two hr intervals) were investigated in mice. MPTP caused shivering, lacrimation, salivation, teeth chattering and fur erection a few minutes after drug injection, but all these behavioural changes were normalized within 30 min., when the first behavioural testing was performed. No significant alteration in general behaviour, sensorimotor performance or body temperature could be detected at the time of nociceptive testing. The acute effects of MPTP on nociception were a reduced response latency in the tail flick test and a prolonged response latency compared to controls in the constant temperature hot plate test. No significant effects of MPTP were found in the increasing temperature hot plate test. The long term effects were a reduced response latency both in the tail flick test and the constant temperature hot plate test, indicating that the MPTP induced lesions of dopaminergic pathways result in hyperalgesia. In the increasing temperature hot plate test and the formalin test, no significant long term changes were demonstrated. Seven days after injection, the dopamine content was reduced to 62% of control values in striatum, to 51% in the rest of the forebrain, and to 41% in the spinal cord. Noradrenaline levels were only slightly and transiently reduced. Serotonin levels were not affected 7 days after injection, but 14 days after injection, a great increase was found in the forebrain and in the spinal cord. The results suggest that dopaminergic systems tonically inhibit nociception.(ABSTRACT TRUNCATED AT 250 WORDS)

The increasing-temperature hot-plate test: an improved test of nociception in mice and rats.

The increasing-temperature hot-plate test has several advantages compared to the conventional hot-plate test, but available equipment has been impractical and restricted with regard to stimulus control. We now describe an apparatus consisting of an aluminum plate that is heated and cooled by Peltier elements in contact with its lower surface. Several plates can be used simultaneously, individually controlled by electronic proportional feedback circuits. The set temperature of the feedback circuit is controlled by a computer program run on an IBM XT-compatible PC, so that a linear increase in temperature is achieved. Experiments were performed using rats and mice, with hindpaw licking as an end-point criterion. Experiments with various heating rates showed that 3.0 degrees C/min is the lowest rate that can be applied without signs of stress in the animals. On the basis of the recorded data, nociceptive temperature thresholds were calculated to be approximately 44.5 degrees C for both rats and mice. Inspection of the paws after analgesic treatment and exposure to different end-point temperatures suggested that a cutoff temperature of 50 degrees C should be employed to minimize tissue damage. Testing at ambient temperatures of 18 degrees and 28 degrees C yielded similar results for rats, whereas mice responded at significantly higher plate temperatures in the colder environment. Dose-related antinociceptive effects were demonstrated for morphine and paracetamol in both species. The results confirm that the increasing-temperature hot-plate test is a valuable test of nociception, which is also suitable for demonstrating the antinociceptive effects of nonopioid analgesics. The test may also be used to estimate the nociceptive temperature threshold.

Benzodiazepine-induced antagonism of opioid antinociception may be abolished by spinalization or blockade of the benzodiazepine receptor.

The mechanisms underlying benzodiazepine antagonism of opioid antinociception were studied using the tail flick test and the hot plate test in mice. Both single-dose and repeated diazepam treatment antagonized the antinociceptive effect of morphine. The specific benzodiazepine antagonist flumazenil completely reversed the antagonism between diazepam and morphine. Mid-thoracic spinalization also abolished the antagonism, indicating that the antagonism takes place at higher levels in the CNS. Neither diazepam nor midazolam showed any affinity for opioid mu or kappa receptors in membranes prepared from mouse forebrain. Taken together with the results of other studies of interactions between GABAergic drugs and opioids, the results indicate that a benzodiazepine receptor-mediated mechanism at higher levels in the CNS, possibly in the brainstem, blocks the effect of opioids on nociceptive transmission.

1,4-Benzodiazepines antagonize opiate-induced antinociception in mice.

The influence of diazepam, midazolam, and flunitrazepam on the antinociceptive effect of morphine, fentanyl, and buprenorphine was studied using the hot-plate test and the tail-flick test in mice. Diazepam and midazolam induced a dose-dependent attenuation of the effect of all three opiates in both tests of nociception. Flunitrazepam antagonized the antinociceptive effect only in the tail-flick test. The benzodiazepine effect could not be explained by altered tail-skin temperature. The antagonism did not correlate well with the sedative or muscle-relaxing properties of the benzodiazepines, and a different mechanism may therefore be involved. It is proposed that the antagonism represents an interaction between benzodiazepines and opioid systems in the brain participating in modulation of nociceptive inputs.

The effect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations.

The effect of (+/-), (+) and (-)-nefopam on the uptake of 5-hydroxytryptamine (5-HT), noradrenaline and dopamine in synaptosomal preparations from rat forebrain, hippocampus and striatum has been investigated. All three forms of nefopam inhibited the amine uptake in the investigated structures, the order of potency being (+) greater than (+/-) greater than (-). (+)-Nefopam was 7-30 times more potent than (-)-nefopam. The same order of potency has also been found for the antinociceptive effect of these three forms, however, the differences were smaller. Inhibition of 5-HT and noradrenaline uptake may not be the sole mechanism underlying the analgesic effect of nefopam.

Diazepam attenuates morphine antinociception test-dependently in mice.

The influence of diazepam on the antinociceptive effect of morphine was studied using four different nociceptive tests in mice. In the tail flick test, diazepam induced a dose-dependent reduction of the morphine effect, with an almost total reversed morphine effect following diazepam 2 mg/kg. The effect could not be explained by altered tail skin temperature or pharmacokinetic changes. Diazepam 1 mg/kg and higher induced sedation and significantly impaired the performance in a rotarod test, a dose of 0.5 mg/kg diazepam was therefore used in the other nociceptive tests. This dose of diazepam significantly attenuated the antinociceptive effect of morphine in the constant temperature hot plate test and the tail flick test. In the increasing temperature hot plate test and in the formalin test, no effect of diazepam on the nociceptive effect of morphine was observed. The results indicate that diazepam antagonizes the effect of morphine dependent upon the test employed. No antagonism could be observed in tests with a long-lasting stimulus, and a response integration probably at a rather high level in the CNS. In the two tests showing antagonism, the stimulus is more short-lasting, and at least for the tail flick test, the integration takes place at a lower level in the CNS.

Both single-dose and repeated administration of clomipramine reduces the behavioural response to intrathecal capsaicin in mice.

Capsaicin injected intrathecally releases substance P from primary sensory nerve endings, and induces a pain related behaviour in mice consisting of licking, biting and scratching directed to the distal part of the body. This behavioural response was reduced by approximately 35% after intraperitoneal administration of clomipramine, 10 mg/kg, 1 hr in advance, and by 38% after repeated administration (10 mg/kg/day for 9 days). Twenty-four hr after the last repeated clomipramine injection, the response after capsaicin was still reduced by 36%, indicating a long-lasting effect of repeated treatment. The results indicate that clomipramine has analgesic properties against pain of central origin both after single-dose and repeated administration.

The role of tail skin temperature in the facilitation of the tail-flick reflex after spinal transection or interference with descending serotonergic neurotransmission.

We examined in mice whether tail skin temperatures and tail-flick reflexes were changed after spinal transection or intrathecal (i.th.) injection of the serotonin (5-HT) neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) or the 5-HT receptor antagonist metergoline. Transection of the spinal cord reduced tail-flick latency (the time needed to evoke the tail-flick reflex by radiant heat) and increased tail skin temperature 15-21 days after surgery. Analysis of covariance showed that the effect of tail skin temperature on tail-flick latency was far more pronounced than the effect of spinal transection. Intrathecal injection of 5,6-DHT (5 or 10 micrograms mouse-1), which extensively reduced the spinal levels of 5-HT, reduced tail-flick latency and increased tail skin temperature 1-5 days after treatment. Similarly, tail-flick latency was shortened and tail skin temperature elevated 15 min after i.th. injection of metergoline (0.5 micrograms mouse-1). Analysis of covariance showed no significant effect of i.th. 5,6-DHT or i.th. metergoline on tail-flick latency. Tail skin temperature, on the other hand, had a highly significant effect on tail-flick latency. The results show that the facilitation of the tail-flick reflex in spinally transected mice and mice injected i.th. with 5,6-DHT or metergoline is mainly caused by increased tail skin temperature. The data do not indicate that descending 5-HT pathways tonically inhibit the tail-flick reflex.

Mechanisms of orphenadrine-induced antinociception in mice: a role for serotonergic pathways.

The possible involvement of central serotonergic pathways in the mechanism of action of orphenadrine citrate was investigated in male albino mice. Orphenadrine (20 mg/kg) did not alter the concentration of 5-hydroxytryptamine (5-HT) or its metabolite 5-hydroxyindole acetic acid in the frontal cortex or spinal cord, nor did it, in moderate concentrations, inhibit the uptake of [14C]5-HT, [3H]noradrenaline ([3H]NA) or [3H]dopamine ([3H]DA) into crude synaptosomal preparations from the cortex. The antinociceptive effect of orphenadrine was studied in the formalin test and in the increasing temperature hot plate test. No sensorimotor impairment was observed for doses of 30 mg/kg or lower. A general depletion of serotonin by means of p-chlorophenylalanine significantly reduced the effect of orphenadrine in both tests, while lesion of the ascending serotonergic systems by means of p-chloroamphetamine did not affect the analgesia. It is concluded that the antinociceptive effect of orphenadrine may be mediated in part via the raphe-spinal serotonergic systems.

Pharmacological manipulation with the descending serotonergic system or transection of the mouse spinal cord has no effect on ependymal ultrastructure.

In order to investigate an effect of descending nerve fibres on mouse spinal cord ependymal ultrastructure, pharmacological manipulation with the serotonergic system or transection of the spinal cord was done. Biochemical analysis showed an 83% reduction of serotonin content in spinal cord tissue after p-chlorophenylalanine injections and a 93% reduction after transection. However, none of the experimental animals showed changes in ependymal ultrastructure compared to control animals as revealed by electron microscopy.