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- Dosing considerations with transdermal formulations of fentanyl and buprenorphine for the treatment of cancer pain. [Journal Article, Review]
- J Pain Res 2014.:495-503.
Opioids continue to be first-line pharmacotherapy for patients suffering from cancer pain. Unfortunately, subtherapeutic dosage prescribing of pain medications remains common, and many cancer patients continue to suffer and experience diminished quality of life. A large variety of therapeutic options are available for cancer pain patients. Analgesic pharmacotherapy is based on the patient's self-report of pain intensity and should be tailored to meet the requirements of each individual. Most, if not all, cancer pain patients will ultimately require modifications in their opioid pharmacotherapy. When changes in a patient's medication regimen are needed, adequate pain control is best maintained through appropriate dosage conversion, scheduling immediate release medication for withdrawal prevention, and providing as needed dosing for breakthrough pain. Transdermal opioids are noninvasive, cause less constipation and sedation when compared to oral opioids, and may improve patient compliance. A relative potency of 100:1 is recommended when converting the patient from oral morphine to transdermal fentanyl. Based on the limited data available, there is significant interpatient variability with transdermal buprenorphine and equipotency recommendations from oral morphine of 75:1-110:1 have been suggested. Cancer patients may require larger transdermal buprenorphine doses to control their pain and may respond better to a more aggressive 75-100:1 potency ratio. This review outlines the prescribing of transdermal fentanyl and transdermal buprenorphine including how to safely and effectively convert to and use them for those with cancer pain.
- Pharmacogenomic study of the role of the nociceptin/orphanin FQ receptor and opioid receptors in diabetic hyperalgesia. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Aug 25.
Targeting functionally independent receptors may provide synergistic analgesic effects in neuropathic pain. To examine the interdependency between different opioid receptors (µ-opioid peptide [MOP], δ-opioid peptide [DOP] and κ-opioid peptide [KOP]) and the nociceptin/orphanin FQ peptide (NOP) receptor in streptozotocin (STZ)-induced diabetic polyneuropathy, nocifensive activity was measured using a hot plate test in wild-type and NOP, MOP, DOP and KOP receptor knockout mice in response to the selective receptor agonists Ro65-6570, morphine, SNC-80 and U50488H, or vehicle. Nocifensive activity was similar in non-diabetic wild-type and knockout mice at baseline, before agonist or vehicle administration. STZ-induced diabetes significantly increased heat sensitivity in all mouse strains, but MOP, DOP and KOP receptor knockouts showed a smaller degree of hyperalgesia than wild-type mice and NOP receptor knockouts. For each agonist, a significant antihyperalgesic effect was observed in wild-type diabetic mice (all P<0.05 versus vehicle); the effect was markedly attenuated in diabetic mice lacking the cognate receptor compared with wild-type diabetic mice. Morphine was the only agonist that demonstrated near-full antihyperalgesic efficacy across all non-cognate receptor knockouts. Partial or near-complete reductions in efficacy were observed with Ro65-6570 in DOP and KOP receptor knockouts, with SNC-80 in NOP, MOP and KOP receptor knockouts, and with U50488H in NOP and DOP receptor knockouts. There was no evidence of NOP and MOP receptor interdependency in response to selective agonists for these receptors. These findings suggest that concurrent activation of NOP and MOP receptors, which showed functional independence, may yield an effective and favourable therapeutic analgesic profile.
- Use of non-opioid analgesics as adjuvants to opioid analgesia for cancer pain management in an inpatient palliative unit: does this improve pain control and reduce opioid requirements? [JOURNAL ARTICLE]
- Support Care Cancer 2014 Aug 29.
Cancer pain is complex, and despite the introduction of the WHO cancer pain ladder, few studies have looked at the prevalence of adjuvant medication use in an inpatient palliative medicine unit. In this study, we evaluate the use of adjuvant pain medications in patients admitted to an inpatient palliative care unit and whether their use affects pain scores or opiate dosing.In this retrospective observational study, patients admitted to the inpatient palliative care unit over a 3-month period with a diagnosis of cancer on opioid therapy were selected. Data pertaining to demographics, diagnosis, oral morphine dose equivalent of the opioid at the time of discharge, adjuvant analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and pain scores as reported by nurses and physicians were collected.Seventy-seven patients were eligible over a 3-month period, out of which 65 (84 %) were taking an adjuvant medication. The most commonly prescribed adjuvant was gabapentin (70 %). Fifty-seven percent were taking more than one adjuvant. There were more women in the group receiving adjuvants (57 vs. 17%, p = 0.010). Those without adjuvants compared with those on adjuvants did not have worse pain scores on discharge as reported by physicians (0.8 ± 0.8 vs. 1.0 ± 0.7, p = 0.58) or nurses (2.0 ± 2.7 vs. 2.1 ± 2.6, p = 0.86). There was no difference in morphine equivalent doses of the opioid in both groups (median (min, max); 112 (58, 504) vs. 200 (30, 5,040)) at the time of discharge; 75-80 % of patients had improvement in pain scores as measured by a two-point reduction in numerical rating scale (NRS).This study shows that adjuvant medications are commonly used for treating pain in patients with cancer. More than half of study population were on two adjuvants or an adjuvant plus NSAID along with an opioid. We did not demonstrate any benefit in terms of improved pain scores or opioid doses with adjuvants, but this could reflect confounding variables and physician choice. Larger prospective studies are needed to define the opioid-sparing effects of adjuvants.Adjuvant agents are used in over 80 % of those treated for cancer pain.
- [Intraoperative esmolol infusion reduces postoperative analgesic consumption and anaesthetic use during septorhinoplasty: a randomized trial]. [English Abstract, Journal Article]
- Rev Bras Anestesiol 2014 Sep-Oct; 64(5):343-9.
Esmolol is known to have no analgesic activity and no anaesthetic properties; however, it could potentiate the reduction in anaesthetic requirements and reduce postoperative analgesic use. The objective of this study is to evaluate the effect of intravenous esmolol infusion on intraoperative and postoperative analgesic consumptions as well as its effect on depth of anaesthesia.This randomized-controlled double blind study was conducted in a tertiary care hospital between March and June 2010. Sixty patients undergoing septorhinoplasty were randomized into two groups. History of allergy to drugs used in the study, ischaemic heart disease, heart block, bronchial asthma, hepatic or renal dysfunction, obesity and a history of chronic use of analgesic or β-blockers were considered cause for exclusion from the study. Thirty patients received esmolol and remifentanil (esmolol group) and 30 patients received normal saline and remifentanil (control group) as an intravenous infusion during the procedure. Mean arterial pressure, heart rate, and bispectral index values were recorded every 10min. Total remifentanil consumption, visual analogue scale scores, time to first analgesia and total postoperative morphine consumption were recorded.The total remifentanil consumption, visual analogue scale scores at 0, 20 and 60min, total morphine consumption, time to first analgesia and the number of patients who needed an intravenous morphine were lower in the esmolol group.Intravenous infusion of esmolol reduced the intraoperative and postoperative analgesic consumption, reduced visual analogue scale scores in the early postoperative period and prolonged the time to first analgesia; however it did not influence the depth of anaesthesia.
- [Adding 75 mg pregabalin to analgesic regimen reduces pain scores and opioid consumption in adults following percutaneous nephrolithotomy]. [English Abstract, Journal Article]
- Rev Bras Anestesiol 2014 Sep-Oct; 64(5):335-42.
Adding novel adjunctive drugs like gabapentinoids to multimodal analgesic regimen might be reasonable for lessening postoperative pain scores, total opioid consumption and side effects after percutaneous nephrolithotomy. We aimed to evaluate the effect of pregabalin on postoperative pain scores, analgesic consumption and renal functions expressed by creatinine clearance (CrCl) and blood neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (Cys C) levels in patients undergoing percutaneous nephrolithotomy (PCNL).60 patients undergoing elective PCNL were enrolled in the study. Patients were randomized to oral single dose 75 mg pregabalin group and a control group. Visual Analog Scale pain scores (VAS), postoperative intravenous morphine consumption during the first 24 postoperative hours, serum NGAL, Cys C levels and creatinine clearance (CrCl) was measured preoperatively and post-operatively at 2nd and 24th hour.Postoperative VAS scores were significantly decreased in the pregabalin group at the postoperative 30th min, 1st, and 2nd hour (p = 0.002, p = 0.001 and p = 0.027, respectively). Postoperative mean morphine consumption was statistically significantly decreased for all time intervals in the pregabalin group (p = 0.002, p = 0.001, p = 0.001, p = 0.001, p < 0.001, respectively). No statistically significant differences were found between the two groups with regard to CrCl, or Cys C at preoperative and postoperative 2nd and 24th hour. Postoperative 24th hour NGAL levels were significantly decreased in the pregabalin group (p = 0.027).Oral single-dose preemptive 75 mg pregabalin was effective in reducing early postoperative pain scores and total analgesic consumption in patients undergoing PCNL without leading to hemodynamic instability and side effects.
- Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone. [Journal Article]
- BMC Palliat Care 2014.:42.
Opioid-induced constipation (OIC) is one of the major symptoms in palliative care with a prevalence of 30-50%. Methylnaltrexone for the treatment of OIC is significantly more effective than placebo, but only in about fifty percent of the patients regardless of dose increase. Dose increases cause increased toxicity without additional efficacy, and are therefore not recommended. While methylnaltrexone is a μ-receptor antagonist, only a few opioids are solely μ-receptor agonists. Therefore, the response to methylnaltrexone may be determined by the receptor-profile of a specific opioid. In addition, methylnaltrexone may also affect the immune system and angiogenesis as was found in pre-clinical studies. Primary aim of this study is to determine differences in the efficacy of methylnaltrexone prescribed to resolve opioid induced constipation between three commonly used opioid subtypes: morphine sulphate, oxycodone and fentanyl. Secondary aim is to explore potential immunomodulatory and antiangiogenic effects of methylnaltrexone.In this multi-center, prospective, parallel group trial we will evaluate the efficacy of methylnaltrexone in resolving OIC occurring as a side effect of the most common opioid subtypes: morphine, oxycodone and fentanyl. In total 195 patients with OIC despite prophylactic laxatives will receive methylnaltrexone every other day up to fourteen days. Patients will report its effect in a laxation diary. Group allocation is based on the opioid type the patient is using. At the start and end of the study period patients complete the Bowel Function Index questionnaire. A subgroup of the patients will donate blood for analysis of immunomodulatory- and anti-angiogenic effects of methylnaltrexone.In this study we aim to determine the efficacy of methylnaltrexone per opioid subtype to reduce constipation. We expect that the outcome of this study will improve the clinical use of methylnaltraxone.This trial is registered at clinicaltrials.gov: NCT01955213 and in the Dutch trial register: NTR4272.
- Buprenorphine for Cancer Pain: Is It Ready for Prime Time? [JOURNAL ARTICLE]
- Am J Hosp Palliat Care 2014 Aug 27.
Buprenorphine (BUP) is a semisynthetic derivative of the opium alkaloid thebaine found in the poppy Papaver somniferum. Its chemical structure contains the morphine structure but differs by having a cyclopropylmethyl group. Buprenorphine is a potent µ opioid agonist. Buprenorphine undergoes extensive first-pass metabolism in the liver and gut. The development of a transdermal BUP formulation in 2001 led to its evaluation in cancer pain. This article provides the practitioner with an update on the current role of BUP in cancer care. It highlights data suggesting effectiveness in various types of cancer pain. The article reviews pharmacology, routes of administration, adverse effects, drug interactions, and cost considerations.
- Inhibition of Apomorphine-induced Conditioned Place Preference in Rats Co-injected with Buspirone: Relationship with Serotonin and Dopamine in the Striatum. [JOURNAL ARTICLE]
- Brain Res 2014 Aug 23.
Apomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist to produce psychostimulant like effects. Currently, apomorphine is used in patients with advanced Parkinson's disease, for the treatment of persistent and disabling motor fluctuations, but a constellation of addictive syndromes such as excessive over use of medication, compulsive behaviors, and disturbances of impulse control are noticed in certain patients. Research on rodent models using conditioned place preference (CPP) paradigm also shows that the drug is rewarding. Previously we have shown that repeated administration of apomorphine produces behavioral sensitization which is prevented in rats co-injected with a low (1.0mg/kg) but not higher (2.0mg/kg) dose of buspirone. The present study shows that rewarding effects of apomorphine (1.0mg/kg) in a CPP paradigm are also blocked in rats co-injected with a low (1.0mg/kg) but not higher (2.0mg/kg) dose of buspirone. The levels of serotonin and its metabolite are decreased in the caudate as well as nucleus accumbens of rats exhibiting CPP and the decreases do not occur in animals co-injected with low or higher dose of buspirone. The levels of dopamine and its metabolites are not affected in animals exhibiting CPP; administration as well as co-administration of higher dose of buspirone decreased dopamine metabolism in the caudate as well as nucleus accumbens. The findings suggest a critical role of serotonin in the rewarding effects of apomorphine and imply that co-use of buspirone at low doses can help to control addictive syndromes in Parkinson's disease patients on apomorphine therapy.
- Bio-inspired solid phase extraction sorbent material for cocaine: A cross reactivity study. [Journal Article]
- Talanta 2014 Dec.:382-7.
The binding specificity of a bio-inspired hexapeptide (QHWWDW) versus cocaine and four other drugs such as 3,4-methylenedioxy-N-methylamphetamine (MDMA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), phencyclidine and morphine was computationally studied and then experimentally confirmed in solid phase extraction (SPE) followed by liquid chromatography-mass spectrometry (LC/MS) detection. In simulation, the hexapeptide-drug complexes were docked with different scoring functions and considering pH chemical environment. In experimental, the cross reactivity of the selected hexapeptide was tested as SPE sorbent versus cocaine and other four drugs using buffer solutions at pH 4 and 7. Significant differences in specific retention were found between cocaine (97% of recovery) and both morphine (45% of recovery) and phencyclidine (60% of recovery), but less for ecstasies (average recovery 69%). In agreement with docking simulation, the hexapeptide showed the highest recovery with best specificity versus cocaine at pH 7 with an experimentally binding constant of 2.9×10(6)M(-1). The bio-inspired sorbent material analytical performances were compared with a commercial reversed phase cartridge confirming the hexapeptide specificity to cocaine and validating simulated data.
- Relativistic Force Field: Parametric Computations of Proton-Proton Coupling Constants in (1)H NMR Spectra. [JOURNAL ARTICLE]
- J Org Chem 2014 Aug 26.
Spin-spin coupling constants in (1)H NMR carry a wealth of structural information and offer a powerful tool for deciphering molecular structures. However, accurate ab initio or DFT calculations of spin-spin coupling constants have been very challenging and expensive. Scaling of (easy) Fermi contacts, fc, especially in the context of recent findings by Bally and Rablen (Bally, T.; Rablen, P. R. J. Org. Chem. 2011, 76, 4818), offers a framework for achieving practical evaluation of spin-spin coupling constants. We report a faster and more precise parametrization approach utilizing a new basis set for hydrogen atoms optimized in conjunction with (i) inexpensive B3LYP/6-31G(d) molecular geometries, (ii) inexpensive 4-31G basis set for carbon atoms in fc calculations, and (iii) individual parametrization for different atom types/hybridizations, not unlike a force field in molecular mechanics, but designed for the fc's. With the training set of 608 experimental constants we achieved rmsd <0.19 Hz. The methodology performs very well as we illustrate with a set of complex organic natural products, including strychnine (rmsd 0.19 Hz), morphine (rmsd 0.24 Hz), etc. This precision is achieved with much shorter computational times: accurate spin-spin coupling constants for the two conformers of strychnine were computed in parallel on two 16-core nodes of a Linux cluster within 10 min.