High Doses Of Morphine Research Articles

Effects of Morphine and Midazolam on Sleep-Wake Cycling in Amplitude-Integrated Electroencephalography in Post-Surgical Neonates ≥32 Weeks of Gestational Age

Background: Studies of children who undergo major non-cardiac surgery in the neonatal period are needed so that subsequent abnormal neurodevelopment can be better understood. Objective:It was the aim of our study to describe the influence of analgesic and sedative medication on the predominant background pattern and the development of sleep-wake cycling (SWC), as measured on amplitude-integrated electroencephalography (aEEG), in newborn infants born ≥32 weeks’ gestation after major non-cardiac surgery. Methods:This prospective study included infants ≥32⁺⁰ weeks’ gestation admitted to the Neonatal Intensive Care Unit at The Royal Children’s Hospital in Melbourne who were undergoing major non-cardiac surgery. Data on morphine and midazolam given after surgery were recorded and the BrainZ Monitor was applied post-operatively. The maximum levels of morphine and midazolam were assessed as predictors of time to aEEG outcomes using linear regression. Results: Forty-seven eligible infants were included. Emergence of SWC was observed at a mean of 13 h after surgery. The maximum dose of morphine or midazolam was not predictive of time to either any or developed SWC. Conclusions: Despite high doses of morphine and midazolam, SWC was observed on aEEG in neonates ≥32 weeks’ gestational age soon after major non-cardiac surgery. The aEEG background pattern was not affected by the maximum dose of either morphine or midazolam.

Withdrawal of Invasive Home Mechanical Ventilation in Patients with Advanced Amyotrophic Lateral Sclerosis: Ten Years of Danish Experience

Due to the growing use of home mechanical ventilation in amyotrophic lateral sclerosis (ALS), physicians are increasingly confronted with patients seeking discontinuation of therapy. Yet there are few systematic investigations of the withdrawal of invasive home mechanical ventilation (IHMV). This article aims to describe the medical and patient-related aspects of terminating IHMV in patients with advanced stage ALS. A retrospective, descriptive study was made of all ALS patients cared for at our center from 2002 to 2009 who decided to withdraw their consent for IHMV. All 12 ALS patients (4 females) received continuous IHMV. They had a median age of 61 years (range, 39-69 years). In all cases advance directives for end of life care, particularly concerning withdrawal of treatment, were discussed before the initiation of IHMV. The median time from initiation of IHMV to the decision to terminate treatment was 22 months (range, 1-35 months). The reasons for requests were for all patients a general loss of "meaning in life." Deep sedation was achieved with high dose morphine and diazepam before disconnecting the ventilator. Patients' requests for the withdrawal of IHMV in advanced stage ALS was related to a perceived "loss of meaning in life." Termination of treatment was performed under deep sedation as a medically, legally, and ethically justified procedure.

Pain management with morphine: variation in analgesic response secondary to genetic polymorphisms

Correspondence: Shailendra Kapoor 2300 E Cary St Richmond, VA 23223, USA Tel +1 804 2342345 Fax +1 804 3454561 Email shailendrakapoor@yahoo.com To the editor The recent article by Villesen et al in a recent issue of your journal was most interesting. Recent studies show that the potency of morphine in efficacious pain control may be influenced greatly by polymorphisms of certain genes. For instance, Klepstad et al have recently shown that cancer patients on opioid maintenance therapy who are homozygous for the variant G allele of the 118 A . G polymorphism of the mu opioid receptor (OPRM1) gene require higher doses of morphine for efficacious pain control in comparison with patients who are heterozygous. In fact, the morphine requirement is almost 93% less in AA genotypes in contrast with morphine requirements in cancer patients who carry the GG genotype of the OPRM1 gene. Similar pain modulation variation is seen with polymorphisms of the OPRM1 gene and perioperative fentanyl administration. Furthermore, more profound CNS depressant side effects after morphine administration are noticed in cancer patients with certain polymorphisms of the multidrug resistance-1 gene. Similarly, the potency of morphine in pain management in cancer patients is influenced and varies greatly with polymorphisms of the catechol-O-methyl transferase gene. For instance, individuals with the Met/Met genotype of the catechol-O-methyl transferase gene require 63% less morphine in comparison with those who have the Val/Val genotype of the catechol-O-methyl transferase gene. More profound central nervous system side effects are seen following morphine administration in cancer patients with single nucleotide polymorphisms in intron 1 of the catechol-O-methyl transferase gene. The above examples clearly illustrate the variation in adequate pain control with morphine secondary to genetic mutations. Further research is needed to identify other similar gene polymorphisms that may affect opioid requirements in patients being managed with other nonmorphine narcotics.

Validation and usefulness of the Danish version of the Pain Medication Questionnaire in opioid‐treated chronic pain patients

Addiction is a feared complication of long-term opioid therapy for chronic pain patients. A screening tool to assess the potential risk of addiction may be helpful. The Pain Medication Questionnaire (PMQ) was translated into Danish by a 'forward' and 'backward' translation procedure. Patients with chronic non-cancer pain and cancer pain treated at a tertiary pain center were screened for addiction using Portenoy's criteria and invited to answer the Danish version of the PMQ. Two hundred nine patients participated in the study. PMQ was able to discriminate between addicted and non-addicted patients. Patients with high PMQ scores indicating a risk of addiction drank more alcohol, smoked more tobacco, used higher doses of morphine, had a higher anxiety and depression score, and had poorer mental health. Using a cut-off score of 22, the PMQ had a sensitivity of 82%, but the specificity at this cut-point was 56%, indicating a risk of false positive cases. Convergent and discriminant validity were confirmed by correlation with opioid doses, alcohol and tobacco use, anxiety and depression scores, and inverse correlation with mental health and social role. Test-retest showed a very strong correlation. Cronbach's alpha for internal consistency was 0.61. Ten components were found to have eigenvalues above 1.0, confirming the multidimensional structure of the questionnaire. The PMQ may assist physicians in addiction risk assessment and stratification when treating chronic pain patients with opioids. PMQ is not a diagnostic tool and should only be used as an indicator for possible addiction problems.

Regulation of human sperm motility by opioid receptors

The endogenous opioid system has been reported to have important functions in human reproduction. Practically all the components of this peptide system have been discovered in human sperm cells, but their functions in these cells are far from being well understood. In the present work, we report the effects of opioid agonism and antagonism on human sperm motility, a parameter which is crucially associated with male fertility. Morphine (10(-7) M), a μ- opioid receptor agonist, decreased both the percentage of motile progressive sperm and three measured velocities without altering the linearity, straightness or vigour of sperm cells. This effect was reversed by naloxone. Higher doses of morphine did not have further effects on the measured parameters. The incubation of sperm cells with the δ-opioid receptor agonist D-penicillamine (2,5)-enkephalin did not affect sperm cell motility. However, naltrindole, a specific δ-receptor antagonist, reduced the linear and curvilinear velocities, as well as linearity, straightness and the amplitude of head displacement, and beat frequency. In summary, our results indicate that the endogenous opioid system may regulate opioid motility in vitro. These finding suggest that the endogenous opioid system could be useful as a biochemical tool for the diagnosis and treatment of male infertility.

Drug discrimination in pigeons trained to discriminate among morphine, U50488, a combination of these drugs, and saline

This study compared fixed-ratio (FR) and fixed-interval (FI) schedules to investigate the discriminative stimulus properties of μ-opioid and/or κ-opioid receptor agonists. Pigeons were trained to discriminate among morphine (μ agonist), U50488 (κ agonist), the combination, and saline under FR 20-s or FI-300-s schedule. After training, correct-key responding averaged 94.4 (FR) and 66.5% (FI) after administration of training drugs. Dose-response curves were generally quantal under the FR and graded under the FI schedules, but highly variable among subjects under the FI. Under the FR schedule, the dose of naltrexone that blocked morphine's discriminative stimuli also blocked U50488. Combining high doses of morphine with low doses of U50488 produced responding on the morphine key and combining high doses of U50488 with low doses of morphine produced responding on the U50488 key. Combining high doses of both drugs produced responding on the drug-combination key. Increasing d,l-pentazocine doses shifted responding from the saline key to the U50488 key, then to the morphine key, and finally to the drug-combination key. Butorphanol and ethylketocyclazocine produced similar effects, except responding on the morphine key increased before responding on the U50488 key. The four-choice procedure under the FR schedule has the potential for determining the discriminative stimulus effects of mixed agonists.

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

AimOpioid 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. MethodsIn 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 14days. Primary outcome was average PI day 3. Secondary outcomes were PI now and AEs day 3 and 14 and number of SAEs. ResultsTwenty one patients were randomised to each group, 16 (SAG) and 19 (3DS) patients received methadone. The mean preswitch morphine doses were 900mg/day in SAG and 1330mg/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. ConclusionThe 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.

Morphine-Modulated Mast Cell Migration and Proliferation during Early Stages of Zymosan-Induced Peritonitis in CBA Mice

We have previously shown that supplementation of inflammation-inducing zymosan with a high dose ofmorphine inhibits peritoneal influx ofleukocytes in Swiss, C57C3H, Balb/c, and C57BL/6 strains but not in CBA mice. We have also reported that the different pattern of the response to morphine treatment might be, at least partially, due to the inter-strain differences in the peritoneal mast cell (P-MC) number (high in CBA mice versus other strains) and P-MC specific features (high sensitivity to degranulation upon morphine treatment in CBA mice). The aim of the present study was to investigate the mechanism of morphine action on P-MC in CBA mice. In particular, the effects of morphine on the proliferation and migration of P-MC in CBA mice with ongoing zymosan-induced peritonitis modulated by morphine were studied. Morphine alone acted as a strong chemoattractant for P-MC of CBA mice and this effect was opioid receptor-independent. Moreover, flow cytometric analysis showed that i.p. morphine injection induced significant proliferation of P-MC in CBA mice. Therefore, we conclude that the lack of anti-inflammatory effects of morphine during peritonitis in CBA mice might result not only from a unique sensitivity of CBA mast cells to morphine-induced degranulation but also from the fact that mast cell numbers increase at the inflammatory focus. The latter might be due to morphine-induced mast cell proliferation and/or migration.

A retrospective analysis of 15 patients with advanced cancer receiving continuous subcutaneous pump injection of high-dose morphine

ObjectiveTo explore the feasibility and efficacy of continuous subcutaneous pump injection of high-dose morphine for cancer pain relief by retrospectively analyze 15 patients who had received this pain relief therapy during 2005 to 2010. Methods We inserted a catheter subcutaneously into the periumbilical tissue, calculated the total daily dose of morphine, selected a Baxter pump to continually administer morphine according to the speed of infusion. We adjusted the dosage of morphine use based on the changes in pain level. Results The total response rate for pain relief was 100%. 11 of the 15 patients(73.3%)had complete relief and the remaining 4(26.7%)had partial relief. Conclusions Continuous subcutaneous pump injection of high-dose morphine for pain relief is reliable in patients with advanced cancer and had slight side effects. It is worth popularizing. Key words: Morphine; Subcutaneous pump injection; Cancer; Pain

Increased pain perception and attenuated opioid antinociception in paradoxical sleep-deprived rats are associated with reduced tyrosine hydroxylase staining in the periaqueductal gray matter and are reversed by L-DOPA

Paradoxical sleep deprivation (PSD) increases pain sensitivity and reduces morphine antinociception. Because dopaminergic neurons in the periaqueductal gray matter (PAG) participate in pain modulation and opioid-induced antinociception, we evaluated the effects of PSD on thermal pain sensitivity, morphine- and L-DOPA-induced antinociception and dopaminergic functionality in the PAG by assessing tyrosine hydroxylase (TH) immunoreactivity. Rats that were subjected to 96h of PSD received vehicle, morphine (2.5, 5 or 10mg/kg), L-DOPA (50 or 100mg/kg) or L-DOPA (50mg/kg)+morphine (2.5 and 5mg/kg) and were tested with a 46°C hot plate 1h after. The paw withdrawal latency responses to the hot plate were decreased in PSD rats and were modified by the highest dose of morphine, L-DOPA and L-DOPA+morphine. Analgesic effects were observed in control groups for all of the morphine doses as well as 100mg/kg of L-DOPA and L-DOPA (50mg/kg)+morphine (5mg/kg). The number of cell bodies that were immunopositive for TH in the PAG was reduced in PSD rats. In conclusion, increased thermal sensitivity was reversed by L-DOPA and could be caused by a reduction TH levels in the PAG. Our data also suggest a relationship between central dopaminergic networks and opiate-induced analgesia in rats.

Orally administered kappa but not mu opiate agonists enhance gastric emptying of a solid canned food meal in dogs.

The effects of oral administration of selective mu (D-Ala2, N-Me-p-nitro-Phe4, Gly5-ol-DAGO, morphine) and/or kappa (3,4 dichloro-N-methyl N [2-(1. fyrrolidinyl) cyclohexyl]-benzene acetamide-U-50488, tifluadom) or mixed agonist (N-desmethyltrimebutine) opioid on gastric emptying have been evaluated using a radiolabelled [57Co] canned food meal in dogs fitted with gastric cannulas. In control conditions (placebo) the percentage of solids emptied 1 h after feeding was 27.3 +/- 4.1%. When given orally at doses of 0.01 to 0.5 mg kg-1, U-50488 increased significantly (P less than 0.05) by 29.1 to 60.8% in a dose-related manner (r-0.94, P less than 0.01) the amount of gastric emptying of the meal in 1 h. This effect was reproduced by oral administration of tifluadom (0.01 to 0.1 mg kg-1) and by N-desmethyltrimebutine (0.1 to 1 mg kg-1). In contrast, the gastric emptying was unaffected by DAGO and morphine at low doses (0.01 and 0.1 mg kg-1) but significantly (P less than 0.05) slowed with higher doses of morphine. The increases in amount of gastric emptying induced by tifluadom, U-50488 and N-desmethyltrimebutine were abolished by previous administration of naloxone (0.1 mg kg-1 i.v.) and [(3-furylmethyl) noretazocine]-MR 22-66 (0.1 mg kg-1 i.v.). These results indicate that orally administered kappa, but not mu agonists at doses not exceeding 1 mg kg-1 enhance the amount of gastric emptying of a solid meal in dogs and suggest that this is due to a selective local stimulation of kappa mucosal or submucosal opiate receptors at antroduodenal level.

Opiate-receptor mediated changes in monoamine synthesis in rat brain.

Abstract The effects of morphine, β-endorphin, naloxone and naltrexone on the rate of tyrosine and tryptophan hydroxylation were investigated in vivo by measuring the accumulation of dopa and 5-hydroxytryptophan (5-HTP) in different brain regions of rats after inhibition of the aromatic L-amino acid decarboxylase. The cerebral concentrations of tyrosine and tryptophan were also measured. Morphine (3–30 mg kg−1) increased the accumulation of dopa dose-dependently (25–50%) in the dopamine-rich areas (limbic forebrain and corpus striatum). In the noradrenaline-predominant parts of the brain (containing hemispheres, diencephalon and lower brain stem) only the highest dose of morphine (30 mg kg−1) significantly increased dopa formation (47%). Similarly to morphine, intracerebroventricularly injected β-endorphin (5–10 βg per rat) increased the formation of dopa. This increase was doubled in limbic forebrain, corpus striatum and cerebral hemispheres. Doses of 10 to 20 μg of β-endorphin were needed to increase dopa accumulation in the diencephalon and the lower brain stem. Naloxone antagonized the β-endorphin-induced increases in dopa. But naloxone and naltrexone (10–100 mg kg−1) decreased the dopa formation in the dopamine-rich areas (about 20–25 %) but not in the noradrenaline-predominant areas. Morphine (30 mg kg−1) and β-endorphin (5 μg per rat) increased the accumulation of 5-HTP whereas naloxone and naltrexone (10 mg kg−1) tended to decrease its formation. Morphine and β-endorphine increased the concentrations of tyrosine and tryptophan, and naloxone decreased the cerebral tryptophan concentration. These results show that the effects of a narcotic agonist (morphine) and of pure narcotic antagonists (naloxone and naltrexone) on the synthesis of dopamine and 5-HT are opposite to each other. Furthermore, the effects of β-endorphine on brain monoamine synthesis are remarkably similar to those of morphine. Thus, it is probable that opiate receptors and their endogenous ligands are involved in the regulation of dopamine and 5-HT synthesis.

Dose Conversion in Opioid Rotation from Continuous Intravenous Infusion of Morphine Hydrochloride Injection to Fentanyl Patch in the Management of Cancer Pain

Opioid rotation has been proposed for management of cancer pain. No studies directly investigating dose equivalence between morphine injection (continuous IV administration) and the transdermal fentanyl patch have been reported. Therefore, we examined dose conversion ratios in patients undergoing opioid rotation from morphine injection to fentanyl patches. The subjects consisted of 45 patients admitted to Kitasato University East Hospital. Medical records were consulted to determine the "basic dose of morphine injection immediately prior to rotation" and the "basic dose of fentanyl patch after rotation". Equivalent doses and conversion ratios obtained with the expression of (daily dose of morphine injection (mg)/daily delivered dose of fentanyl patch (mg)) were determined from the relationship between the data by regression analysis. The regression equation obtained was Y=50.882X-13.96, r²=0.8922, where X and Y are daily doses of morphine injection and fentanyl patch, respectively. Equivalent doses and conversion ratios for daily dose of morphine injection (mg): daily delivered dose of fentanyl patch (mg) (patch dose mg/3 days) were 16.6 mg: 0.6 mg (2.5 mg)=28:1, 47.1 mg: 1.2 mg (5 mg) = 39:1 and 169.2 mg: 3.6 mg (15 mg)=47:1. In other reports, the ratio of morphine vs. fentanyl at 50:1 had no relation to the dose. While the present study suggested that in opioid rotation from low dose, 50:1 is not enough for the fentanyl patch. The dose conversion ratio of morphine injection to fentanyl patch was different at the low doses and high doses of morphine.

The Infusion of Opioids During Terminal Withdrawal of Mechanical Ventilation in the Medical Intensive Care Unit

Context Most deaths in intensive care units occur after limitation or withdrawal of life-sustaining therapies. Often these patients require opioids to assuage suffering; yet, little has been documented concerning their use in the medical intensive care unit. Objectives To determine the dose and factors influencing the use of opioids in patients undergoing terminal withdrawal of mechanical ventilation in this setting. Methods Data were prospectively collected from 74 consecutive patients expected to die soon after extubation. The doses of morphine, effect on time to death, and relation of dose to diagnostic categories were analyzed. Results The mean (±standard deviation) dose of morphine given to patients during the last hour of mechanical ventilation was 5.3 mg/hour. Patients dying after extubation received 10.6 mg/hour just before death. Immediately before extubation, the dose correlated directly with chronic medical opioid use and sepsis with respiratory failure and inversely with coma after cardiopulmonary resuscitation or a primary neurological event. After terminal extubation, the final morphine dose correlated directly with the presence of sepsis with respiratory failure and chronic pulmonary disease. The mean time to death after terminal extubation was 152.7 ± 229.5 minutes without correlation with premorbid diagnoses. After extubation, each 1 mg/hour increment of morphine infused during the last hour of life was associated with a delay of death by 7.9 minutes ( P = 0.011). Conclusion Premorbid conditions may influence the dose of morphine given to patients undergoing terminal withdrawal of mechanical ventilation. Higher doses of morphine are associated with a longer time to death.

The rat intervertebral disk degeneration pain model: relationships between biological and structural alterations and pain

IntroductionDegeneration of the interverterbral disk is as a cause of low-back pain is increasing. To gain insight into relationships between biological processes, structural alterations and behavioral pain, we created an animal model in rats.MethodsDisk degeneration was induced by removal of the nucleus pulposus (NP) from the lumbar disks (L4/L5 and L5/L6) of Sprague Dawley rats using a 0.5-mm-diameter microsurgical drill. The degree of primary hyperalgesia was assessed by using an algometer to measure pain upon external pressure on injured lumbar disks. Biochemical and histological assessments and radiographs of injured disks were used for evaluation. We investigated therapeutic modulation of chronic pain by administering pharmaceutical drugs in this animal model.ResultsAfter removal of the NP, pressure hyperalgesia developed over the lower back. Nine weeks after surgery we observed damaged or degenerated disks with proteoglycan loss and narrowing of disk height. These biological and structural changes in disks were closely related to the sustained pain hyperalgesia. A high dose of morphine (6.7 mg/kg) resulted in effective pain relief. However, high doses of pregabalin (20 mg/kg), a drug that has been used for treatment of chronic neuropathic pain, as well as the anti-inflammatory drugs celecoxib (50 mg/kg; a selective inhibitor of cyclooxygenase 2 (COX-2)) and ketorolac (20 mg/kg; an inhibitor of COX-1 and COX-2), did not have significant antihyperalgesic effects in our disk injury animal model.ConclusionsAlthough similarities in gene expression profiles suggest potential overlap in chronic pain pathways linked to disk injury or neuropathy, drug-testing results suggest that pain pathways linked to these two chronic pain conditions are mechanistically distinct. Our findings provide a foundation for future research on new therapeutic interventions that can lead to improvements in the treatment of patients with back pain due to disk degeneration.

Place aversion by morphine in offspring born of female morphine administered wistar rats.

This research was designed to study sexual differences in place conditioning induced by morphine in offspring born of female Wistar rats mated with drug-naïve males. Mothers were exposed to morphine during the 14(th)-16(th) days of gestational. Control dams were simply saline-injected. Female and male virgin offspring born of morphine-treated or saline-treated mothers were separately housed until become fully matured. A 3-day schedule of an unbiased conditioning procedure was used to the induce conditioning to morphine (2.5-7.5 mg/Kg, SC) in the offspring. According to the results, female offspring born of saline-administered mothers were morphine place-conditioned at lower doses of opioid (2.5 mg/Kg) in comparison to the males. An increase in locomotor activity in the females at 7.5 mg/Kg of opioid was also revealed. In contrast, administration of morphine (2.5-7.5 mg/Kg, SC), induced a significant aversion in either sexes of offspring born of morphine-exposed mothers. Moreover, female offspring of this category acquired more pronounced aversion at higher doses of morphine than males. In addition, a significant morphine-dose effect (7.5 mg/Kg, SC) on locomotor activity of these females' offspring was observed. This study may highlight sex differences in conditioning effects induced by morphine between offspring derived of morphine-treated mothers and those of saline-treated.

Difficulties in Controlling Mobilization Pain Using a Standardized Patient-Controlled Analgesia Protocol in Burns

The aim of this study was to evaluate pain relief for patients with burns during rest and mobilization with morphine according to a standard protocol for patient-controlled analgesia (PCA). Eighteen patients with a mean (SD) burned TBSA% of 26 (20) were studied for 10 days. Using a numeric rating scale (NRS, 0 = no pain and 10 = unbearable pain), patients were asked to estimate their acceptable and worst experienced pain by specifying a number on a scale and at what point they would like additional analgesics. Patients were allowed free access to morphine with a PCA pump device. Bolus doses were set according to age, (100 - age)/24 = bolus dose (mg), and 6 minutes lockout time. Degrees of pain, morphine requirements, doses delivered and demanded, oral intake of food, and antiemetics given were used as endpoints. Acceptable pain (mean [SD]) was estimated to be 3.8 (1.3) on the NRS, and additional treatment was considered necessary at scores of 4.3 (1.6) or more. NRS at rest was 2.7 (2.2) and during mobilization 4.7 (2.6). Required mean morphine per day was 81 (15) mg, and the number of doses requested increased during the first 6 days after the burn. The authors found no correlation between dose of morphine required and any other variables. Background pain can be controlled adequately with a standard PCA protocol. During mobilization, the pain experienced was too intense, despite having the already high doses of morphine increased. The present protocol must be refined further to provide analgesia adequate to cover mobilization as well.

Use of Methadone for Uncontrolled Pain: An Alternative Dosing Regimen

Use of Methadone for Uncontrolled Pain: An Alternative Dosing Regimen

Effect of expression of P-glycoprotein in tumor tissue on analgesic efficacy of morphine and buprenorphine in advanced cancer patients with pain

Objective To evaluate the effect of the expression of P-glycoprotein （P-gp） in tumor tissue on analgesic efficacy of morphine and buprenorphine in advanced cancer patients with pain. Methods One hundred and fifty advanced cancer patients with pain aged 51-64 yr weighing 54-65 kg were included in this study. The expression of P-gp was negative in the tumor tissue in 50 patients （group M1 and B1, n = 25 each） and positive in 100 patients （group M2 ,M3 ,and B2 ,B3, n =25 each）. The PCA regimen for the 6 groups were listed in the table .Pain was assessed with VAS scores （0 = no pain, 10 = worst pain） and venous blood samples were taken for determination of blood morphine/buprenorphine concentrations at 4, 12, 24 and 48 h of PCIA. Results The six groups were comparable with respect to age, body weight, M/F sex ratio, types of cancer, baseline pain level and education. The analgesic efficacy of morphine and buprenorphine was better （ VAS scores were significantly lower）in P-gp expression negative patients （group M1 and B1 ） than in P-gp expression positive patients （group M2 and B2 ）. Higher doses of morphine and buprenorphine provided better analgesic efficacy in P-gp expression positive patients in group M3 and B3 than in group M2 and B2. Plasma morphine and buprenorphine concentrations were comparable between group M1 , B1 and M2, B2 and were significantly higher in group M3 and B3 at each time point. Conclusion Positive P-gp expression in the tumor tissue can decrease the analgesic efficacy of morphine and buprenorphine in advanced cancer patients with pain. Key words: Glycoproteins; Morphine; Buprenorphine; Neoplasms; Analgesia

Genetic deletion of pleiotrophin leads to disruption of spinal nociceptive transmission: Evidence for pleiotrophin modulation of morphine-induced analgesia

Pleiotrophin (PTN) is a growth factor that exhibits neurotrophic actions and is upregulated at sites of nerve injury. Upregulation of PTN levels in injured dorsal root ganglion correlates with decreased mechanical allodynia and faster recovery from Chronic Constriction Injury of the rat sciatic nerve. Despite the evidence pointing to a role of PTN in the development of chronic pain, the role of this neurotrophic factor in pain transmission has not been assessed in acute pain models. We have now studied the behaviour of PTN genetically deficient (PTN−/−) and wild type (PTN+/+) mice in the hot-plate and tail-immersion tests. We found that basal central pain responses do not differ between PTN−/− and PTN+/+ mice in the hot-plate test. Very interestingly, basal latencies to a tail flick were significantly increased in PTN−/− mice as assessed in the tail-immersion test. It was also aimed to evaluate morphine-induced analgesia in PTN−/− and PTN+/+ mice. We did not find differences among genotypes using a high dose of morphine (10 mg/kg) in the hot-plate test, reaching this dose the analgesia peak 25 min after injection (i.p.) and returning to almost basal values 125 min after injection. In contrast, we found that an intermediate dose of morphine (5 mg/kg) significantly delayed pain responses in PTN−/− mice compared to PTN+/+ mice in both the hot-plate and tail-immersion tests. The data strongly suggest that PTN is of critical importance for pain processing at the spinal level and, furthermore, that endogenous PTN modulates morphine-induced analgesic effects in mice.