A systematic review of qualitative research exploring patient and health professional perspectives of breakthrough cancer pain.

PURPOSE: Breakthrough cancer pain (BtCP) is a prevalent health issue which is difficult to manage. A plethora of quantitative research in this area exists. There is a paucity of research on the perspectives of health professionals and patients surrounding domains impacting effective treatment, including definitions of BtCP, treatment, and education opportunities. This review aims to identify and synthesize the extent of qualitative research exploring health professional and patient perspectives of BtCP. METHODS: A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach was undertaken. The approach was registered with Prospero. MEDLINE, EMBASE, and Web of Science were searched for peer-reviewed literature published any date prior to May 19, 2022. Eligible sources must have considered health professional and/or patient perspectives of BtCP. A narrative synthesis approach was utilized. RESULTS: Three sources met the review criteria. One source explored nurse perspectives, while two sources explored patient perspectives. Study quality was moderate to high. Overlapping themes across the three studies included communication, defining BtCP, impact of BtCP, management of BtCP, perceptions of BtCP, analgesia and pain relief, and training and professional development. CONCLUSION: Given limited research investigating clinician and patient perspectives of BtCP, a rich understanding informed by exploratory qualitative methods around identification, best management strategies, professional development, and factors promoting and inhibiting best practice remains unclear. Further qualitative inquiry is warranted, and it is expected such research will inform BtCP clinical guidelines.

Central mechanisms of stress-induced headache.

Stress is the most commonly reported trigger of an episode of chronic tension-type headache (CTTH); however, the causal significance has not been experimentally demonstrated to date. Stress may trigger CTTH through hyperalgesic effects on already sensitized pain pathways in CTTH sufferers. This hypothesis could be partially tested by examining pain sensitivity in an experimental model of stress-induced headache in CTTH sufferers. Such examinations have not been reported to date. We measured pericranial muscle tenderness and pain thresholds at the finger, head and shoulder in 23 CTTH sufferers (CTH-S) and 25 healthy control subjects (CNT) exposed to an hour-long stressful mental task, and in 23 CTTH sufferers exposed to an hour-long neutral condition (CTH-N). Headache developed in 91% of CTH-S, 4% of CNT, and 17% of CTH-N subjects. Headache sufferers had increased muscle tenderness and reduced pain thresholds compared with healthy controls. During the task, muscle tenderness increased and pain thresholds decreased in the CTH-S group compared with CTH-N and CNT groups. Pre-task muscle tenderness and reduction in pain threshold during task were predictive of the development and intensity of headache following task. The main findings are that stress induced a headache in CTTH sufferers, and this was associated with pre-task muscle tenderness and stress-induced reduction in pain thresholds. The results support the hypothesis that stress triggers CTTH through hyperalgesic effects on already increased pain sensitivity in CTTH sufferers, reducing the threshold to noxious input from pericranial structures.

Reliability of temporal summation and diffuse noxious inhibitory control.

BACKGROUND: The test-retest reliability of temporal summation (TS) and diffuse noxious inhibitory control (DNIC) has not been reported to date. Establishing such reliability would support the possibility of future experimental studies examining factors affecting TS and DNIC. Similarly, the use of manual algometry to induce TS, or an occlusion cuff to induce DNIC of TS to mechanical stimuli, has not been reported to date. Such devices may offer a simpler method than current techniques for inducing TS and DNIC, affording assessment at more anatomical locations and in more varied research settings. METHOD: The present study assessed the test-retest reliability of TS and DNIC using the above techniques. Sex differences on these measures were also investigated. RESULTS: Repeated measures ANOVA indicated successful induction of TS and DNIC, with no significant differences across test-retest occasions. Sex effects were not significant for any measure or interaction. Intraclass correlations indicated high test-retest reliability for all measures; however, there was large interindividual variation between test and retest measurements. CONCLUSION: The present results indicate acceptable within-session test-retest reliability of TS and DNIC. The results support the possibility of future experimental studies examining factors affecting TS and DNIC.

Effect of cimetidine on renal and hepatic drug elimination: studies with triamterene.

A chronic-dosing pharmacokinetic study was carried out in six healthy subjects to examine the potential for cimetidine to reduce the CLR and CLH of triamterene. Blood and urine samples were collected frequently for 24 hours after dosing with triamterene alone (100 mg/day) for 4 days and concomitant cimetidine (400 mg twice daily) for an additional 4 days. Cimetidine significantly reduced the clearance of triamterene by hydroxylation by 32% (P less than 0.016) and the CLR of triamterene by 28% (P less than 0.063), with no change in its protein binding. The CLR of the active sulfate conjugate of triamterene was not altered by cimetidine. There was a reduced recovery of triamterene and its metabolites in urine after cimetidine, suggesting a decreased absorption. These results are consistent with cimetidine inhibiting cytochrome P-450 enzymes in the liver and also competing with triamterene for renal tubular secretion. Despite the pharmacokinetic interaction, cimetidine caused minimal alteration to the natriuretic and antikaliuretic effects of triamterene.

The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women.

OBJECTIVE: Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of migraine. In this study we investigated the cardiovascular and central nervous system effects and the pharmacokinetics of zolmitriptan in young and elderly adults. METHODS: Twelve young adult and 12 elderly volunteers received single doses of 5, 10, and 15 mg zolmitriptan during a randomized, double-blind, placebo-controlled study. Blood pressure, heart rate, ECG, and central nervous system effects were monitored, and pharmacokinetic parameters of zolmitriptan and its metabolites calculated. RESULTS: Zolmitriptan did not affect heart rate and had little effect on systolic blood pressure in the young adults. In the elderly, mean peak supine systolic blood pressure values were 9 to 16 mm Hg higher after zolmitriptan than after placebo. Mean peak diastolic pressure was 6 to 10 mm Hg higher in both age groups. These changes were transient. Postural changes in blood pressure were unaffected. There was a dose-related increase in sedation, but the magnitude of the effects was small. Mean observed peak plasma concentration (Cmax) and area under the plasma concentration-time profile [AUC(0-infinity)] for zolmitriptan and its active N-desmethyl metabolite were similar in both age groups but higher in young women than in young men. Metabolite/parent ratios probably the result of greater first-pass metabolism in young men. Zolmitriptan half-life was 2.8 to 3.6 hours in the elderly compared with 2.7 to 2.9 hours in young adults. Mean Cmax and AUC(0-infinity) for the inactive, N-oxide, and the indole acetic acid metabolites were higher in the elderly, associated with lower renal clearance. CONCLUSIONS: Zolmitriptan was well tolerated, with an effect of age on its effects on blood pressure and the pharmacokinetics of its metabolites. The data suggest no need for dose adjustment for age. In young subjects, concentrations were higher in women than in men, but the differences were insufficient to justify dosage adjustment.

Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function. METHODS: Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg. RESULTS: Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four. CONCLUSION: A dose reduction by a factor of six is recommended for persons with severe renal failure.

Pharmacokinetics of valsartan in patients with liver disease.

OBJECTIVES: Valsartan (CGP 48933), an orally active angiotensin II antagonist, is eliminated mainly by hepatic clearance. To characterize the compound(s) excreted in the bile, biliary excretion of valsartan was investigated by collection of bile after an intravenous dose of valsartan. In addition, to determine the exposure to valsartan when liver function is impaired, a pharmacokinetic study (open, single dose) was performed in patients with mild and moderate impairment of liver function. PATIENTS: Biliary excretion of valsartan (after intravenous administration of 20 mg valsartan) was assessed in a patient who underwent a hepaticojejunostomy with subsequent bile drainage. Exposure to valsartan in patients with mild (n = 6) or moderate (n = 6) impaired liver function (Child's-Pugh classification) and matching (sex, age, and weight) healthy volunteers (n = 12) was studied after oral administration of a single dose of 160 mg valsartan. RESULTS: After intravenous administration, valsartan was eliminated mainly as unchanged drug in the bile. Mean exposure (measured as area under the plasma valsartan concentration-time curve) to valsartan was increased about twofold in both the mild and the moderate groups compared with matched (age, sex, and weight) healthy volunteers. CONCLUSION: These data are consistent with the pharmacokinetics of valsartan in that biliary excretion is the main route of elimination.

Pharmacokinetics of new antiherpetic agents.

Valaciclovir and famciclovir, two new prodrugs (for aciclovir and penciclovir, respectively) have similar pharmacokinetics in many regards. Both have good but incomplete bioavailability, with the conversion to the active forms taking place in the liver, but by different cytosolic enzymes. Absorption and conversion are consistent in relevant patient groups, including those with liver disease. The pharmacokinetics of both active molecules are also similar in being mainly renally eliminated, a significant component of which is tubular secretion, and elimination half-lives from plasma of approximately 2.2 to 2.5 hours. Dosage adjustment is required in the presence of renal impairment. No clinically important drug interactions have been identified with either drug. The choice between the two agents is likely to depend on clinical factors such as tolerability, safety, efficacy, compliance and possibly cost, rather than on their pharmacokinetics.

Lack of an effect of zolmitriptan (Zomig, 311C90) on psychometric task performance: results of a placebo-controlled study in healthy volunteers.

The novel selective 5-hydroxytryptamine (5-HT)1B/1D agonist, zolmitriptan (Zomig, formerly known as 311C90), has shown good efficacy in the acute oral treatment of migraine. Zolmitriptan acts both centrally and peripherally, therefore it is important to assess central nervous system effects. At single doses of 25-50 mg (up to 8 times the likely therapeutic dose), zolmitriptan can cause sedation; therefore, a study was designed to examine the dose-response. A double-blind, randomized, placebo-controlled, six-limb crossover study in 13 healthy volunteers compared the effects of single oral doses of zolmitriptan (5, 10, 15 or 20 mg) and lorazepam (2 mg) on various psychometric tests. Zolmitriptan doses less than 20 mg had no statistically significant effects on choice reaction time, the Stroop test, visual analog scale (VAS) assessments of physical sedation, tranquilization and other types of feelings, the logical reasoning test or the adaptive tracking test. There was a mild transient increase in the subjective assessment on VAS of mental sedation which was dose related and occurred mainly with the highest zolmitriptan dose and were not reflected in objective measures of drug effects. In contrast, lorazepam (used as a positive control) was associated with statistically significant impairment in all tests (except tranquilization) for up to 10 h after dosing. The results demonstrate that therapeutic doses of zolmitriptan are unlikely to cause clinically significant impairment in psychometric performance.

Effect of citalopram on plasma levels of oral theophylline.

BACKGROUND: Citalopram and theophylline may be prescribed together to treat patients with depression and asthmatic disease. Because theophylline has a low therapeutic index, small changes in plasma levels may result in therapeutic failure or adverse effects. Both citalopram and theophylline are metabolized by cytochrome P450 (CYP) isozymes. Theophylline is metabolized by CYP1A2; however, the extent to which citalopram interacts with this isozyme in vivo is not known. OBJECTIVE: This study was conducted to investigate whether citalopram alters plasma levels of oral theophylline. METHODS: In an open-label, multiple-dose study, healthy nonsmoking volunteers 18 to 45 years of age were administered a single oral dose of theophylline (300 mg) on day 1. Beginning on day 3, citalopram 40 mg was administered daily through day 24 to achieve steady-state plasma levels. On day 23 a single oral dose of theophylline 300 mg was coadministered with citalopram 40 mg. Fasting plasma levels of theophylline were measured on day 1 (in the absence of citalopram) and on day 23 (in the presence of steady-state plasma concentrations of citalopram) periodically for 36 hours. RESULTS: Thirteen subjects (8 men and 5 women) participated; all completed the study. One subject was not included in the pharmacokinetic calculations. Citalopram treatment had no effect on the pharmacokinetic characteristics of theophylline. CONCLUSIONS: Citalopram dosing to steady state did not inhibit or induce the metabolism of theophylline in this population of healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with citalopram.

Bioequivalence between ready-to-use recombinant human growth hormone (rhGH) in liquid formulation and rhGH for reconstitution.

The bioequivalence of recombinant human growth hormone (rhGH) for reconstitution, at either 24 IU or 8 mg, and three strengths of liquid formulation of rhGH (5, 10 or 15 mg per 1.5 ml, hGH) was tested in two randomized, single-blind, four-period, crossover studies in healthy subjects. The study drugs were administered by subcutaneous injection at a dose of 2.5 mg rhGH/m(2)body surface area or as a fixed dose of 5 mg rhGH. Endogenous hGH release was suppressed by a continuous somatostatin infusion. The 90% confidence intervals for the estimated mean ratios of AUC(0-24 h)and C(max)(analysis of variance) between all products were within 80-125% in both studies. Also, no significant differences (P> 0.05; Wilcoxon signed rank test) were found between t(max)for the liquid formulations of rhGH. These data demonstrate that there is bioequivalence between rhGH for reconstitution and the liquid formulations of rhGH.

Simultaneous investigation of indinavir nonlinear pharmacokinetics and bioavailability in healthy volunteers using stable isotope labeling technique: study design and model-independent data analysis.

Indinavir follows nonlinear pharmacokinetics upon oral administration at clinical doses. A study employing the stable isotope administration technique in a three-treatment design was conducted to identify the source of the nonlinearity and to determine the dose-dependency of systemic bioavailability. In treatment A, 400 mg of unlabeled indinavir (D0) was coadministered orally with 16 mg of a hexadeutero analogue of indinavir (D6) intravenously. In treatment B, 800 mg of D0 po was coadministered with 16 mg of D6 intravenously. In treatment C, 16 mg of iv D6 was infused concurrently with 16 mg iv of D0. Plasma concentrations of D0 and D6 were determined by an LC/MS/MS assay method. Concentrations of indinavir in plasma increased greater than dose-proportionally over the 400- to 800-mg dose range. No meaningful kinetic isotope effects were found in treatment C. Plasma concentrations of D6 were dependent on the coadministered D0-indinavir dose and were lowest in treatment C, higher in treatment A, and highest in treatment B. The bioavailability of indinavir was high (60-65%) and comparable between the 400- and 800-mg doses. There was a significant contribution of nonlinear kinetics in the systemic circulation to the observed disproportional increase in plasma concentrations following oral dosing. The high bioavailability at clinically relevant doses suggests a high degree of saturation of first-pass metabolism. These results further demonstrate that the concomitant administration technique in combination with the LC/MS/MS method can provide a realistic and reliable means of elucidating important pharmacokinetic properties of drug candidates during product development.

Comparison of the onset of H1-antagonism with acrivastine and terfenadine by histamine bronchial challenge in volunteers.

The speed of onset of H1-antagonism by 8 mg acrivastine and 60 mg terfenadine was compared by bronchial challenge of volunteers with histamine. Active treatments or placebo were administered 1 or 2 h before challenge in a double-blind, randomized, balanced crossover manner to 10 subjects. Acrivastine and terfenadine significantly attenuated the response to inhaled histamine compared to placebo. The effects of acrivastine at 1 and 2 h before challenge, and terfenadine at 2 h were indistinguishable, but that of terfenadine at 1 h was significantly less, indicating that acrivastine has a faster onset of action than terfenadine.

Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation.

Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(-1)), morphine (20 mg kg(-1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (-9.5 s, P<0.01 and -7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.

Pharmacokinetics and unexpected safety issues of LBM415, a novel oral peptide deformylase inhibitor.

Peptide deformylase (PDF) inhibitors represent a potential new class of antibiotics targeting a large number of bacterial species. We studied the pharmacokinetics and safety of LBM415, a novel PDF inhibitor, administered as a single oral dose at 100-3,000 mg in the fasted state and at 1,000 mg in the fed state in healthy volunteers. LBM415 was then administered at dosages ranging from 100 mg q.d. to 1,000 mg t.i.d. for 11 days. Dose-proportional pharmacokinetics was observed, with a peak plasma concentration (C(max)) of 17.85 ± 5.96 µg/ml at 1,000 mg b.i.d. (the projected therapeutic dose) and an area under the concentration-time curve (AUC)(0-24h) of 36.83 ± 10.36 µg/ml·h. The half-life, as determined after a 1,000-mg single dose, was 2.18 ± 0.61 h. The compound was well tolerated at low doses, but at the highest dose, 1,000 mg t.i.d., reversible cyanosis and low oxygen saturation, attributable to methemoglobinemia, were detected on day 11. Oxygen saturation was as low as 88% in one subject on day 11.

Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease.

Ibudilast is a relatively nonselective phosphodiesterase inhibitor which has been marketed for almost 20 years in Japan for treating asthma. More recently it has been found to have anti-inflammatory activity in both the peripheral immune system and in the CNS via glial cell attenuation. This CNS-directed anti-inflammatory activity is of potential use in the treatment of multiple sclerosis, neuropathic pain, and in the improved efficacy and safety of opioids by decreasing opioid tolerance, withdrawal and reinforcement. Its suitable pharmacokinetics and generally good tolerability make it a promising potential treatment for these conditions.

Potential drug interactions with the novel antimigraine compound zolmitriptan (Zomig, 311C90).

Seven randomized studies in healthy volunteers have investigated interactions between zolmitriptan (Zomig, formerly 311C90), a 5HT1B/1D agonist for acute migraine therapy, and selected drugs with which there was a possibility of interaction or a likelihood of concurrent use. Co-administration of oral dihydroergotamine, ergotamine, pizotifen, fluoxetine, paracetamol (acetaminophen)/metoclopramide or selegiline had no clinically significant effects on the pharmacokinetics of zolmitriptan or its metabolites, although small changes were observed in some cases. Co-administration of propranolol resulted in a 56% increase in the area under the plasma concentration-time curve (AUC) of zolmitriptan and a 11% decrease in the AUC of the active metabolite 183C91. However, these pharmacokinetic changes are unlikely to be relevant at lower clinical doses. Moclobemide, a monoamine oxidase A (MAO-A) inhibitor, decreased the clearance of zolmitriptan and, in particular, 183C91. This suggests that MAO-A is involved in the metabolism of 183C91 and it may be prudent to limit the daily zolmitriptan dose in migraine patients maintained on a MAO-A inhibitor. The clinically insignificant blood pressure increases produced by zolmitriptan, and the tolerability profile of this agent, were unaffected by any of the concomitant medications. Clinically significant interactions between zolmitriptan and commonly co-prescribed antimigraine therapies are unlikely.

Zolmitriptan: a new acute treatment for migraine.

Zolmitriptan is a new oral acute treatment for migraine. It is a selective and potent agonist at the serotonin (5-HT)(1B/1D) receptor and was developed to improve on the oral bioavailability, tissue selectivity and CNS penetration of earlier compounds. Animal studies confirmed that these objectives had been attained. In man, zolmitriptan is rapidly absorbed after oral administration, with at least 75% of the eventual C(max) reached within 1 h. Oral bioavailability is approximately 40%. The elimination half-life of zolmitriptan is approximately 2.5 h and the primary route of elimination is metabolism, with one of the metabolites being pharmacologically active. A consistent 2-h headache response rate of 60-70% was observed at doses of 2.5 mg and above. Long-term treatment response is high (> 80%) and consistent. In addition, there is evidence from electrophysiology in migraineurs that zolmitriptan has a central action not shared by sumatriptan. Zolmitriptan is well-tolerated. The nature and incidence of the most frequently reported adverse events are similar to those of other 5-HT(1B/1D) agonists. Long-term zolmitriptan usage was associated with an improvement in quality of life. Zolmitriptan is a suitable first-line drug for acute treatment for migraine.

The onset of effect of the H1-antagonist acrivastine ("Semprex") assessed by histamine bronchial challenge in volunteers.

The onset of effect of acrivastine, a new H1-antagonist, has been assessed using antagonism of histamine-induced bronchoconstriction in sensitive volunteers. Acrivastine administered 30, 45, 60 or 90 min before challenge produced a right-shift of the histamine dose-response curve of at least 8-fold indicating that a clinically desired degree of H1-antagonism was present within 30 min of ingestion of the recommended therapeutic dose.