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Context: The lack of knowledge of the accurate conversion ratio (CR) between intravenous (IV) and oral hydromorphone and opioid rotation ratio (ORR) between IV hydromorphone and oral morphine equivalent daily dose (MEDD) may lead to poorly controlled pain or overdosing in cancer inpatients., Objectives: We aimed to determine the CR and ORR from IV hydromorphone to oral hydromorphone and MEDD (obtained from oral morphine and oxycodone)., Methods: A total of 4745 consecutive inpatient palliative care consults during 2010-14 were reviewed for conversions from IV hydromorphone to oral hydromorphone, morphine or oxycodone. Patient characteristics, symptoms, and opioid doses were determined in patients successfully discharged on oral opioids without readmission within one week. Linear regression analysis was used to estimate the CR or ORR between the 24 hour IV hydromorphone mg dose before conversion and the oral opioid mg dose used before discharge., Results: Among 394 patients on IV hydromorphone, 147 underwent conversion to oral hydromorphone and 247 underwent rotation to oral morphine (163) or oxycodone (84). The median (interquartile range) CR from IV to PO hydromorphone was 2.5 (2.14-2.75) with correlation of 0.95 (P < 0.0001). The median ORR (interquartile range) from IV hydromorphone to MEDD was 11.46 (9.84-13.00) with correlation of 0.93(P < 0.0001). The median ORR was 11.54 in patients receiving <30 mg of IV hydromorphone/day and 9.86 in patients receiving ≥30 mg (P = 0.0004)., Conclusion: Our study found that 1 mg of IV hydromorphone is equivalent to 2.5 mg of oral hydromorphone and 11.46 mg of MEDD. Hydromorphone at doses ≥30 mg/day may require a lower ORR to other opioids., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Methadone is an important drug in the management of both cancer-related and non-cancer-related pain and is the main pharmacologic agent used in the treatment of opioid addiction. Unexpected hypoglycemia has been observed in patients receiving methadone, prompting a more detailed investigation., Objectives: To evaluate the incidence of hypoglycemia in a cohort of inpatients receiving methadone versus other opioids including fentanyl, hydromorphone, and morphine., Methods: Retrospective observational cohort of inpatients in a tertiary cancer center admitted for more than 48 hours from November 1, 2011 to October 30, 2013. The main outcomes were lowest measured daily blood glucose (in mg/dL) and incidence of hypoglycemia (defined as blood glucose < 70 mg/dL, equivalent to 3.9 mmol/L) with variable methadone doses compared with other non-methadone opioids., Results: Of the 641 eligible patients admitted during the study period who received at least one dose of methadone during admission, multivariable logistic regression showed significant associations between methadone and hypoglycemia at doses greater than 40 mg oral equivalents per day or with patient-controlled analgesia use. A dose-response relationship was observed, with an odds ratio of 3.1 (95% confidence interval 2.5, 3.6) when doses greater than 80 mg/day were used. No evidence of increased risk of hypoglycemia or of a dose-response curve was seen for the other opioids., Conclusion: The risk of hypoglycemia is increased for patients taking more than 40 mg oral methadone equivalents per day. When starting methadone at or more than 40 mg/day, we recommend blood glucose monitoring., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Eliza Coffee Memorial Hospital is a community hospital with a palliative care unit providing inpatient symptom management and end-of-life care. The palliative care unit provides authorized agent controlled analgesia (AACA)., Objectives: The objective of this study was to determine if an AACA system improves control of pain and other end-of-life symptoms adequately and if it provides families with satisfactory involvement in the care of their loved ones., Methods: Data on demographics, pain assessments, length of stay before and after consult, drugs used, mortality, discharge disposition, and family and staff satisfaction were collected by chart review of all 2013 consultations., Results: There was a total of 318 consults in 2013. Of the 118 patients (37% of total) who used the AACA system, 112 (95%) died in hospital; morphine was used by 77% and the others used hydromorphone. Following the patient's death, of the 70 AACA families contacted, 100% were satisfied with the pain/symptom control. Staff also were overwhelmingly pleased with the system., Conclusion: An AACA system has been highly satisfactory for patients, families, and staff, meeting the goals of 1) allowing patients with a terminal condition to die peacefully and 2) enabling families to share in the patients' care, providing them with a more favorable memory at the end of life., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Acute episodic breathlessness in patients receiving palliative care is a distressing symptom with little evidence-base to inform management. This pilot, double-blind, controlled, crossover study compared the effects of nebulized hydromorphone, systemic hydromorphone and nebulized saline for the relief of episodic breathlessness in advanced cancer patients. On three occasions of acute breathlessness, patients randomly received either nebulized hydromorphone, a systemic breakthrough dose of hydromorphone or nebulized saline together with a blinding agent. Breathlessness was scored before and 10, 20, 30, and 60 minutes post-treatment completion using a 100 mm visual analog scale. Twenty patients completed the trial. Ratings did not differ significantly across pretest treatments. Change in ratings from pretest to 10 minutes after completion of nebulization (about 20 minutes after administration of systemic hydromorphone) indicated that each of the treatments resulted in statistically significant improvements in breathlessness, with no significant differences between treatments. Over time, breathlessness decreased significantly for all treatments, with no significant differences between treatments. Only nebulized hydromorphone produced a rapid improvement in breathlessness that reached a magnitude considered to be clinically important. Interpretation of these results is considered in relation to our definition of clinical significance, the dose of hydromorphone used and the possibility of a placebo effect. This study can serve to inform the design of future trials to investigate the management of incident breathlessness.

Two multicenter, randomized, double-blind, crossover studies with identical designs evaluated the efficacy of oral extended-release hydromorphone (HHER) administered q24h compared with immediate-release hydromorphone (HHIR) dosed four times daily in patients with persistent moderate to severe pain. Patients titrated to a stable HHER dose were randomized to individualized doses of HHER or HHIR for 3 to 7 days before crossover to the second treatment. Primary efficacy end point was the mean of average pain intensity (API) scores, rated on a 0- to 10-point numeric scale, over the last 2 days before the pharmacokinetics/pharmacodynamics day of each double-blind period. Difference between treatments (HHER - HHIR) in study 1 was 0.17 with a 90% confidence interval (CI) (-0.01, 0.34); in study 2, difference was 0.07 with a 90% CI (-0.12, 0.26). There were no significant differences between treatments in API scores or amount of rescue medication used at any time interval within the 24-hour dosing period. No reduction in pain control occurred in patients administered HHER at the end of the 24-hour dosing period. Most treatment-emergent adverse events were opioid-related. In these studies, HHER administered q24h and HHIR dosed four times daily provided comparable analgesia at an equivalent total daily dose.

Clonidine is frequently added to opioids in implantable intrathecal pumps for the management of chronic pain. In such devices, a small non-retrievable volume is always present in the reservoir, and its effect on drug stability is unknown. Furthermore, stability of clonidine, when mixed with hydromorphone, has not been previously determined. This study examined the stability of clonidine when co-administered with hydromorphone in implanted intrathecal pumps. Samples of hydromorphone-clonidine before pump refill and from residual solution at subsequent refill were obtained from chronic pain patients. Clonidine concentration was measured using HPLC. Twenty paired samples from 3 patients were analyzed. All 3 patients had a SynchroMed pump implanted for 3-5 years. We found no loss in clonidine concentration during the time between refills (35 +/- 13 days), and no correlation between clonidine concentration and time interval between refills. In conclusion, clonidine, mixed with hydromorphone, is stable when delivered by implantable intrathecal pump for long-term use.

Increasing numbers of patients with refractory pain are receiving intrathecal drug delivery systems (IDDS). We describe a case to illustrate the clinical manifestations and management implications of inadvertent overdose with drugs used in IDDS, including opioids, clonidine, baclofen, and local anesthetics. An IDDS patient received a bimonthly dose of intrathecal hydromorphone subcutaneously. The patient received a total of 540 mg hydromorphone into the subcutaneous pocket around the intrathecal pump. She was treated with naloxone intravenously over 12 hours, and had no major adverse sequelae. Such occurrences may happen more frequently with the expanded use of IDDS and clinicians should be prepared to take quick action. Counteracting an opioid with naloxone until the opioid is metabolized and excreted can be done safely. Inadvertent subcutaneous administration of other types of drugs could be more difficult to manage.

To evaluate the effectiveness of intrathecal clonidine or clonidine/opioid admixture for the treatment of chronic pain states, a retrospective chart audit of 15 patients seen by the Pain Medicine and Neurosurgical Services was performed. Subjects included 9 men and 6 women aged 26-86 years. Diagnoses included complex regional pain syndrome, neuropathic pain, and cancer pain. All patients received a trial of single-shot and/or short-term infusion of clonidine. Those reporting a significant reduction in pain, or at least 50% reduction in their visual analog scale (VAS), received long-term therapy. Intrathecal clonidine as a single-shot dose, infusion, or as intrathecal polytherapy did not improve VAS scales from pre-treatment values in 5 patients. Ten patients reported significant pain relief or >50% decrease in VAS scores with the initial trial and received long-term therapy. Two received clonidine alone for 7-11 months before the therapy failed; others failed after just a few days. Seven of eight initially responded to clonidine alone (75-950 microg/day) before failing and requiring a second drug. Three received hydromorphone (200-8000 microg/day) and four morphine (0.15-15 mg/day) with clonidine. Four patients then failed 2-drug therapy (duration 6-21 months). Two continue with intrathecal clonidine/hydromorphone (duration 19-29 months) and 1 with clonidine/morphine (duration 21 months). After initiation of intrathecal clonidine, one patient reported good relief with clonidine/morphine until his death 5 months later. In this population, intrathecal clonidine was of limited utility for most patients. It may be of benefit for subset(s) of patients, but in our experience, duration of relief is typically <18 months.

The objective of this open-label, repeated-dose, single-treatment, multicenter study was to evaluate the outcomes associated with a standardized conversion from prior opioid therapy to a novel, once-daily, OROS osmotic technology, extended-release (ER) hydromorphone formulation in an outpatient population with chronic malignant or nonmalignant pain. The study period was divided into 3 phases: the prior opioid stabilization phase (> or =3 days), the conversion and titration phase (3-21 days), and the maintenance phase (14 days). Patients were evaluated at 5 visits during the study period. Analgesic efficacy was measured using the Brief Pain Inventory (BPI). At baseline, patients were required to have daily oral morphine equivalent requirements of > or =45 mg. Prior oral or transdermal opioid therapy was converted to single daily doses of ER hydromorphone (8, 16, 32, and 64 mg tablets) at a 5:1 (morphine equivalent to hydromorphone) ratio. Immediate-release (IR) hydromorphone was given as rescue medication for breakthrough pain. Among the 445 patients who enrolled, 404 received the study medication. Of these, 73 (18.1%) had chronic malignant pain and 331 (81.9%) had chronic nonmalignant pain. Dose stabilization (defined as a 3-day period during which the total daily dose of ER hydromorphone remained unchanged and < or =3 doses of IR hydromorphone per day were required) was attained by 73.8% of patients (298/404), of whom 70.1% (209/298) were stabilized with < or =2 titration steps. The mean +/- standard deviation (SD) time to dose stabilization was 12.1 +/- 5.7 days (range of 3 to 33 days). The mean +/- SD final daily dose of ER hydromorphone was 63.4 +/- 129.2 mg. The mean +/- SD final daily dose of IR hydromorphone was 11.5 +/- 36.4 mg, and the mean +/- SD final number of daily doses of IR hydromorphone was 1.7 +/- 1.3. Intent-to-treat and completer analysis demonstrated significant improvements in BPI ratings from prior opioid therapy to the end of ER hydromorphone therapy (P < 0.01 for all pairwise comparisons). Adverse events were consistent with those expected of an opioid agonist in such a patient group, affecting primarily the gastrointestinal and central nervous systems. This uncontrolled study delineates a regimen by which patients with chronic malignant or nonmalignant pain can be readily converted from prior opioid therapy and titrated to an appropriate maintenance dose of ER hydromorphone. Controlled longitudinal studies are required to further evaluate the use of ER hydromorphone in patients with discrete chronic malignant or nonmalignant pain conditions.

With the exception of morphine, hydromorphone is the most commonly used intrathecal opioid for the treatment of intractable pain. The purpose of this study was to evaluate the stability and compatibility of hydromorphone in the implantable infusion system that is most commonly used in these patients. Hydromorphone solution was incubated at 37 degrees C in infusion system reservoirs and with individual materials which comprise the fluid pathway of the infusion system. Stability was analyzed using high performance liquid chromatography; mechanical integrity of device materials was evaluated after drug exposure. After 4 months of exposure to device materials or intact devices, hydromorphone concentration remained greater than 95% of starting material. All device materials retained acceptable mechanical performance. These results demonstrate that hydromorphone is stable at physiological temperatures for at least 4 months in an implantable infusion system and that current clinical practice of refilling the pump every 3 months is appropriate.

Providing pain management for known opioid abusers is a challenging clinical task, in part because little is known about their pain experience and analgesic requirements. This study was designed to describe pain tolerance and analgesic response in a sample of opioid addicts stabilized in methadone-maintenance (MM) treatment (n = 60) in comparison to matched nondependent control subjects (n = 60). By using a placebo-controlled, two-way factorial design, tolerance to cold-pressor (CP) pain was examined, both before and after oral administration of therapeutic doses of common opioid (hydromorphone 2 mg) and nonsteroidal anti-inflammatory (ketorolac 10 mg) analgesic agents. Results showed that MM individuals were significantly less tolerant of CP pain than control subjects, replicating previous work. Analgesic effects were significant neither for medication nor group. These data indicate that MM opioid abusers represent a pain-intolerant subset of clinical patients. Their complaints of pain should be evaluated seriously and managed aggressively.

Seventy-four patients were included in a double-blind, randomized, controlled trial comparing the analgesic efficacy and adverse effects of hydromorphone and morphine delivered by continuous subcutaneous infusion. Patients completed the Memorial Pain Assessment Card and a checklist of opioid-related adverse effects immediately before commencing subcutaneous infusion and 24, 48, and 72 hours later. An assessment tool was developed for the 60 patients who were too ill to complete their own questionnaire. The tool demonstrated excellent inter-rater reliability. Thirty-four percent of patients in the hydromorphone group and 27% of those in the morphine group died before completion of the study (P = 0.66). The hydromorphone group required more analgesia for breakthrough pain in the first 24 hours of the study (P = 0.03) and had a greater improvement in the behavior of frowning on movement and the comfort visual analogue scale (P = 0.08) over the course of the study. Adverse effects were rare and similar in both groups. This study found hydromorphone to be at least as effective as morphine when delivered by continuous subcutaneous infusion.

We report 2 years' experience managing 39 preteen (ages 4-12 years) children with patient-controlled analgesia (PCA) for pain associated with bone marrow transplantation (BMT). We prescribed morphine or hydromorphone PCA (starting bolus 20 micrograms/kg morphine or 2 micrograms/kg hydromorphone) with or without continuous infusion (CI), for a period of 6-74 days. The duration of PCA use (median 19 days) depended upon severity of mucositis or other painful conditions. The peak morphine use was on the 11th day after BMT. We prescribed CI opioids in addition to PCA, either at night or around the clock, in 52% of patients. Ninety-five percent of children successfully mastered PCA to control pain associated with BMT. We observed no instances of drug misuse, parental tampering, accidental overdose, or difficulty weaning from opioids. We conclude that opioid PCA, with or without CI, over several days or weeks is safe and effective for preteen children suffering BMT-related pain.

Altered sexual function has been reported in individuals addicted to opioids or on methadone maintenance, yet little literature is available regarding the effect of intraspinal opioids on libido or sex hormone levels. We evaluated sexual function and plasma sex hormone levels in six men treated with chronic intraspinal opioids. All patients had some reduction in libido and four patients had difficulty obtaining or maintaining an erection. These changes were noted within 1 month of beginning intraspinal opioid therapy. Serum testosterone levels ranged from 26 to 367 ng/dL (normal, 350-1500 ng/dL); the mean serum level was 197.7 ng/dL (SD = 119.8). Serum testosterone levels and other sex hormones, including follicle-stimulating hormone, luteinizing hormone, sex-hormone-binding globulin, and prolactin, should be measured prior to and at various points during intraspinal opioid therapy. Patients should be queried regarding sexual function and should be cautioned regarding the possibility of these adverse effects prior to initiating spinal opioids. Supplemental testosterone should be considered to treat this dysfunction.

In a prospective open study, 24 patients with cancer pain receiving parenteral opioids were administered highly concentrated solutions of hydromorphone in order to assess the local tolerance to the subcutaneous infusion. Patients received a mean concentration of hydromorphone of 30 +/- 15 mg/mL at a mean rate of infusion of 0.3 +/- 0.25 mL/hr. Of 22 evaluable patients, 17 (77%) had a site duration of more than 7 days with their first subcutaneous site (mean concentration of 34 +/- 8 mg/mL of hydromorphone). Four of the five remaining patients (80%) had site duration of more than 7 days with their second subcutaneous site. Only one patient (5%) did not reach a 7-day duration after three consecutive site changes. Out of 7 subcutaneous sites that presented signs of toxicity before 7 days of infusion, the main problem was erythema in three cases, swelling in two cases, and bleeding in two cases. All sites improved spontaneously and did not require any medical treatment. No correlation was found between the concentration or rate of infusion of hydromorphone and the duration of the subcutaneous site. The duration of the site was significantly correlated with weight, tricep skinfold, subscapular skinfold, and age of the patients. Our findings suggest that hydromorphone can be safely administered in concentrations that are much higher than those commercially available. The availability of highly concentrated formulations of different opioids for parenteral use will make home management simpler and cheaper.

Few significant side effects have been reported from the treatment of cancer pain by subcutaneous infusion of opioids. In this prospective year-long study, 8 of 13 patients treated by this technique experienced painful chronic focal toxicity, manifested by induration, erythema and subdermal necrosis during subcutaneous analgesia therapy. A hydraulic-irritation effect is suggested.