Search

Hydromorphone (HM) is a potent opioid analgesic that is commonly administered in the emergency department (ED) and other acute care settings, such as medical surgical wards. In recent years, there has been a significant increase in the ED administration of HM relative to other opioids. Although HM is an effective analgesic, its use has been commonly implicated in adverse drug events and medication errors. In addition, intravenous HM has potent euphoric effects that may contribute to its abuse liability. There are limited data regarding how acute parenteral administration of opioid analgesics in the setting of high rates of preexisting chronic opioid use (medical or nonmedical) may contribute to or reinforce addictive behavior, making the potential contribution of rising HM administration to subsequent prescription opioid abuse and overdose uncertain. This review addresses the pharmacology of HM, recommended dosing, its efficacy for acute pain, as well as its tolerability, safety, and abuse profiles. Controversies and strategies for appropriate use of this medication are also described.

Objective: To assess the reduction in intravenous (IV) abuse potential of hydromorphone from different dose ratio combinations with naloxone in opioid-dependent drug users., Design: Randomized, blinded, dose ratio escalation study., Setting: Single center., Participants: Following conversion to a stable IV dose of hydromorphone, 12 non-treatment-seeking, opioid-dependent subjects were randomly assigned and received at least one dose of study drug; seven subjects received all five study treatments. Five subjects withdrew early from the treatment phase: adverse events (2) and participant decision (3)., Interventions: Participants underwent a dose-selection phase to stabilize on an individualized hydromorphone dose. Stable subjects were dosed intravenously on 5 consecutive days. The dose received was one of five hydromorphone/naloxone dose ratios that included the combination of hydromorphone and placebo naloxone. Hydromorphone/naloxone treatment always involved increasing dose ratios of naloxone (8:1, 6:1, 4:1, and 2:1) with the hydromorphone-placebo naloxone treatment randomly assigned within the sequence of dose ratios., Main Outcome Measures: Drug Liking visual analog scale (VAS), Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS)., Results: Hydromorphone/naloxone placebo produced subjective effects typical of opioid administration, while hydromorphone/naloxone dose ratios were associated with significant increases in SOWS and OOWS scores (p < 0.05). Compared with hydromoprophone/naloxone placebo, naloxone reduced the effects of hydromorphone on most measures, including Drug Liking VAS, the antagonism was greatest for the 4:1 and 2:1 ratios., Conclusions: This study was an ethical investigation of the abuse deterrence potential of four hydromorphone/naloxone dose ratios. The IV coadministration of commercially available IV solutions of hydromorphone and naloxone in 4:1 and 2:1 ratios had statistically greater reductions of abuse-related opioid effects and triggers of withdrawal symptoms and there was a convergence of subjective and objective pharmacodynamic results and safety findings. An oral modified-release product, developed with a 2:1 hydromorphone/naloxone ratio, may have important public health benefits by reducing high-risk, IV abuse of prescription opioids, while providing pain relief when ingested orally and used in accordance with the Product Monograph.

Concurrent administration of oxycodone and phenytoin may cause, through induction of CYP3A4 enzymes, decreased analgesic effects of oxycodone. However, no descriptions of this interaction exist. A patient who was on oxycodone for chronic back pain was admitted to the hospital. Five days after initiating fosphenytoin, the patient experienced a dramatic escalation in his pain and lack of response to oxycodone breakthrough doses. Changing oxycodone to hydromorphone resulted in significantly improved analgesia. Concurrent use of fosphenytoin and oxycodone may increase the conversion of oxycodone to inactive metabolites, resulting in decreased analgesia. This may be avoided using hydromorphone, morphine, or oxymorphone.

Background: Intraspinal drug delivery therapy has been increasingly used in patients with intractable, nonmalignant pain who have failed to respond to conventional treatment or cannot tolerate systemic opioid(s) due to adverse events. By infusing a small dose of an opioid analgesic directly into the cerebrospinal fluid, near opioid receptors, profound spinal analgesia can be obtained. Before the implantation of permanent intraspinal pump, a neuraxial opioid infusion trial is usually conducted to demonstrate the effectiveness of neuraxial opioid for analgesia. Patient-controlled epidural opioid infusion trial, performed in an outpatient setting, is one of the approaches used to conduct such a trial., Objective: To report a case of severe pruritus observed during the continuous epidural hydromorphone infusion trial and to conduct a focused review of the literature., Case Report: An otherwise healthy 56-year-old lady, with a 4-year history of severe low back pain and bilateral leg pain due to failed back surgery syndrome, was referred to our clinic for intraspinal drug delivery therapy. Following a preimplantation psychological evaluation confirming her candidacy, she consented to an outpatient patient-controlled continuous epidural hydromorphone trial. A tunneled lumbar epidural catheter was placed at L3-L4 with catheter tip advanced to L2 under fluoroscopic guidance. Satisfactory catheter placement was confirmed by epidurogram. The catheter was then tunneled subcutaneously and connected to a Microject™ patient-controlled epidural analgesia (PCEA) pump (Codman, Raynham, MA). The pump was programmed to deliver hydromorphone 0.3 mL/h (0.06 mg, concentration 0.2 mg/mL) at basal rate of 0.3 mL/h, with bolus dose set at 0.2 mL (0.04 mg) and 30-minute lockout interval. The patient was instructed how to operate the infusion pump prior to discharging home. During the infusion trial, she reported satisfactory analgesia (>90 percent pain reduction) and was able to reduce her oral opioid dose by more than 80 percent. However, she developed severe, persistent itching, unresponsive to meticulous epidural infusion titration or various antipruritic treatments. Her pruritus remained severe and unabated until a few hours after the termination of the epidural hydromorphone infusion., Conclusion: Pruritus may occur and persist during epidural hydromorphone infusion. This report describes severe pruritus in a patient on epidural hydromorphone administration, in the setting of an outpatient infusion trial.

Objective: The aim of this study was to determine the efficacy and tolerability of hydromorphone extended release (ER) in patients with chronic low back pain (LBP) with or without a neuropathic component., Design: This was a post hoc analysis of data from a multicenter, double-blind, placebo-controlled clinical trial using a randomized withdrawal design, performed in patients with moderate to severe chronic LBP. Patients achieving stable doses of hydromorphone ER during a 2- to 4-week conversion and titration phase were randomized to continue treatment with hydromorphone ER or taper-down to placebo during a 12-week double-blind phase. The primary efficacy outcome was the mean change in 11-point Numeric Rating Scale (NRS) pain intensity score from randomization to the final visit of the double-blind phase. Tolerability was assessed by recording adverse events (AEs). Data were analyzed separately for patients with non-neuropathic and neuropathic LBP., Results: A total of 173 patients with non-neuropathic/nociceptive LBP and 94 with neuropathic LBP were randomized into the double-blind phase. During the conversion and titration phase, mean (SD) NRS scores decreased significantly from 6.5 (1.87) and 6.4 (1.99) at screening to 3.3 (0.98) and 3.2 (1.05), respectively. For both LBP subgroups, patients randomized to hydromorphone ER maintained this improvement over the double-blind treatment period, whereas those randomized to placebo reported significant increase in NRS scores. Across subgroups, the incidence of 1 or more AE was 54 percent to 57 percent in the conversion and titration phase and 47 percent to 55 percent in the double-blind phase., Conclusions: The results of this study indicate that hydromorphone ER is efficacious and generally well tolerated in the management of patients with non-neuropathic and neuropathic chronic LBP.

Objective: To assess the efficacy and safety of once-daily hydromorphone extended-release tablets (OROS [Alza Corporation, Mountain View, CA] hydromorphone ER) in patients with chronic neuropathic pain., Design: Single-center, open-label, 12-week study., Patients: Opioid-tolerant patients with chronic neuropathic pain for $6 months (N = 30)., Interventions: Patients were converted from previous opioid therapy to OROS hydromorphone ER using a 5:1 morphine:hydromorphone equianalgesic dosing ratio, with an initial 50 percent reduction of the calculated equianalgesic dose, titrated every 3-4 days to adequate analgesia over 2 weeks., Outcome Measures: The primary efficacy measure was change from baseline to week 12 (end of study) on question #5 ("average pain") of the Brief Pain Inventory (BPI). Secondary measures included least pain, worst pain, current pain, and sleep interference on the BPI, as well as the Pain Quality Assessment Scale (PQAS) and patient global assessment of treatment satisfaction., Results: Thirty patients were enrolled and received $1 dose of OROS hydromorphone ER, titrated to a final mean dose of 26.4 mg/d. Mean (SE) BPI change from baseline to end of study was -1.3 (0.59) for current pain (p < 0.05) and -1.8 (0.61) for worst pain (p < 0.01). Mean (SE) change from baseline was also significant for BPI scores for sleep interference (-1.7 [0.61]; p < 0.01) and PQAS scores (-24.8 [7.9], p < 0.01). The majority (81 percent) of patients were satisfied or very satisfied with treatment. The most common treatment-related adverse events were dizziness, headache, and nausea (two patients each)., Conclusions: Patients with chronic neuropathic pain were safely and effectively converted to and maintained on OROS hydromorphone ER.

Objective: The reasons providers choose one parenteral opioid over another are not well understood. The authors sought to determine why emergency department (ED) providers choose one parenteral opioid over another., Methods: In a cohort of ED patients who received intravenous morphine or hydromorphone, the authors prospectively assessed patient and provider factors associated with choice of opioid, which were included in regression analyses to identify independent predictors of hydromorphone prescription. Providers were also asked in real time why they chose one opioid over another for a specific patient. Narrative responses were coded and analyzed., Results: Opioid choice was tightly linked with equianalgesic dose, with the median hydromorphone dosage more than 50 percent higher than the dosage of morphine. Besides dose, choice of hydromorphone was most strongly associated with home opioid use and a diagnosis of kidney stone. Provider preference or habit was the most commonly cited reason for choosing the prescribed opioid, with the majority of those responses given by providers who prescribed morphine. One-fourth of morphine prescribers stated that the patient required a lower dosage or less potent option; one-fourth of hydromorphone prescribers stated that either the patient required a higher dosage or more potent option or hydromorphone is more effective. In total, 46 percent of providers gave a reason that does not seem to have pharmacologic validity., Conclusions: ED providers seem to prescribe "usual" dosages of morphine and relatively higher usual dosages of hydromorphone. The reasons for choosing one opioid over the other for a specific patient vary from simple preference to common misconceptions about opioid pharmacology. Improved understanding of opioid pharmacology may improve analgesic outcomes for some patients.

Objective: This analysis was designed to assess the pooled safety and tolerability of once-daily hydromorphone extended release (ER) (OROS® hydromorphone ER) in opioid-naïve and opioid-tolerant patients with chronic cancer or noncancer pain., Design: Safety results were pooled from 13 controlled and uncontrolled clinical studies, with varying approaches to dosing and titration, pain etiology, and duration of exposure., Patients and Interventions: Of the 3,075 patients in the pooled population, 2,335 (76 percent) received at least one dose of OROS hydromorphone ER, with a duration of dosing of up to 1.5 years; 420 patients were treated for at least 6 months and 141 for longer than 1 year., Main Outcome Measures: The primary outcome measure was the occurrence of adverse events (AEs). Descriptive statistics were used to analyze the incidence of AEs in the overall population as well as according to baseline characteristics., Results: Overall AE incidence with OROS hydromorphone ER treatment was 80.5 percent (1,880/2,335 patients). The most common treatment-related AEs were constipation (28.9 percent, 674 patients) and nausea (22.7 percent, 529 patients), and most cases were mild to moderate in severity. The incidence of overall AEs did not undergo a notable change over time. Opioid-related AEs were higher in patients ≥65 years of age, female patients, and opioid-naïve patients. Serious adverse events (SAEs) were reported by 10.2 percent (239) of patients. A total of 64 deaths occurred, none of which were considered related to OROS hydromorphone ER treatment., Conclusions: OROS hydromorphone was generally well tolerated in short- and long-term studies and demonstrated a consistent AE profile over time.

Background: Data on conversion ratios for switching opioids in substitution treatment are limited., Methods: Data were obtained from a randomized controlled trial among long-term opioid-dependent patients conducted in Vancouver and Montreal, Canada. Patients received diacetylmorphine (n = 115) or hydromorphone (n = 25) on a double-blind basis, on a 1:3 potency ratio with individually adjusted dosage, both injectable., Results: Average daily dosages of hydromorphone and diacetylmorphine prescribed were 212.6 mg and 454.0 mg, respectively; potency ratio was 1:2.0-2.2 at different dose ranges., Conclusions: Studies using hydromorphone as a diacetylmorphine equivalent should consider the ratio found in this study to achieve equipotency and maintain the blinding.

Objectives: OROS hydromorphone (osmotic extended-release oral delivery system [OROS] hydromorphone) is a long-acting opioid analgesic, which is approved in Europe for the management of severe pain. The authors aimed to estimate the economic value of this product relative to other widely used oral opioids, including sustained-release morphine, extended-release (ER) oxycodone, and twice-daily (bid) hydromorphone., Design: An adaptable, decision-analytic cost-utility model was developed. Separate versions of the model were developed for five European countries: Germany, Denmark, Slovakia, Portugal, and Italy., Results: OROS hydromorphone represents a cost-effective alternative to other strong oral opioids in the treatment of both nonmalignant and malignant pain in all five countries. In the treatment of chronic severe nonmalignant pain, OROS hydromorphone was dominant (ie, lower cost and incremental quality-adjusted life years gains) when compared with ER oxycodone in Denmark and bid hydromorphone in Germany. Likewise, OROS hydromorphone was dominant in the treatment of chronic severe malignant pain when compared with ER oxycodone in both Germany and Denmark and when compared with bid hydromorphone in all markets where hydromorphone was marketed., Conclusions: This model demonstrates the cost effectiveness of OROS hydromorphone relative to other strong oral opioids in the treatment of chronic severe malignant and nonmalignant pain.

The steady-state pharmacokinetics of an extended-release formulation of hydromorphone, OROS hydromorphone, was investigated in a randomized, open-label, crossover study in healthy volunteers. Participants were randomly assigned to receive 16 mg of OROS hydromorphone once daily and 4 mg of immediate-release hydromorphone four times daily for five consecutive days. The two treatments were separated by a washout period of 7-14 days. Naltrexone was given throughout both treatment periods to block the opioid effects of hydromorphone. Steady-state hydromorphone concentrations were statistically analyzed using Helmert contrasts to determine when steady state was reached. A total of 30 participants were enrolled, of whom 29 completed both treatment periods. The two treatments produced comparable steady-state plasma drug concentrations, but peak-to-trough fluctuations were smaller with OROS hydromorphone (61 percent vs 172 percent) in comparison with immediate release hydromorphone. Overall systemic exposure to hydromorphone was similar between the two formulations. The ratio of the geometric means between the two formulations for the area under the concentration-time curves at steady state was 105.2 percent with a 90% confidence interval (CI) of 99.8-110.8 (geometric mean: 102.7 percent; 90% CI: 97.6-108.2 after correcting for measured drug content), which was within the bioequivalence range (80-125 percent). The analysis of Helmert contrasts showed that steady state conditions were attained by day 4. Both treatments were well tolerated. This study shows that OROS hydromorphone maintains steady-state plasma drug concentrations within the same range as immediate-release hydromorphone at the same total daily dose, with less fluctuation.

Objective: To assess the safety and efficacy of long-term repeated dosing of OROS hydromorphone in chronic pain patients., Design: This multicenter, open-label extension trial enrolled patients from three short-term OROS hydromorphone trials., Setting: Fifty-six centers in the United States and Canada., Patients: Adults with chronic cancer pain or chronic nonmalignant pain who were receiving stable doses of OROS hydromorphone (> or = 8 mg/day). Three hundred and eighty-eight patients were enrolled, 106 patients completed at least 12 months of therapy., Interventions: OROS hydromorphone (individualized doses) was administered once daily., Main Outcome Measures: Safety and efficacy (Brief Pain Inventory and patient and investigator global evaluations) were assessed at monthly visits., Results: The median duration of extended OROS hydromorphone therapy was 274 days. The median daily dose of study medication was 32.0 mg at extension-study baseline, 40.0 mg at month 3, and 48.0 mg at months 6, 9, and 12, respectively. The most frequently reported adverse events were nausea (n = 93, 24.0 percent) and constipation (n = 75, 19.3 percent). The analgesic effects of OROS hydromorphone, assessed using the Brief Pain Inventory, were maintained throughout the extension. At 12 months, 72.4 percent of patients and 75.9 percent of investigators rated overall treatment as good, very good, or excellent., Conclusions: Once-daily OROS hydromorphone is an osmotically driven, controlled-release preparation that may be particularly well suited to long-term use, because it provides consistent plasma concentrations and sustained around-the-clock analgesia. In this study, the benefits of OROS hydromorphone attained in short-term studies were maintained in the long-term when daily administration was continued.

Objective: To evaluate the safety and efficacy of a single dose of 2 mg i.v. hydromorphone administered to emergency department patients in acute severe pain., Design: Prospective interventional., Setting: Urban academic emergency department. PATIENT, PARTICIPANTS: Nonelderly adults (21- 64-years-old) with acute severe pain and baseline oxygen saturation (SO2) > or = 95 percent., Interventions: Two milligrams i.v. hydromorphone administered over 2-3 minutes., Main Outcome Measures: The primary outcome was use of naloxone as a reversal agent. Secondary outcomes included degree of pain relief as measured on a numerical rating scale, frequency of oxygen desaturation (SO2 < 95 percent), and side effects., Results: Of the 269 patients, none received i.v. naloxone. Median pain scores fell from 10 (worst pain possible) at baseline to 1 within 5 minutes and to 0 (no pain) at 30 minutes. SO2 was > or = 95 percent at all time points in 68 percent of patients (95 percent CI 62-73 percent), while 26 percent (95 percent CI 21-32 percent) had one or more SO2 levels between 90-94 percent, and 6 percent (95 percent CI 4-10 percent) had SO2 values below 90 percent at one or more time points. The lowest SO2 was 82 percent. The incidence of nausea and vomiting were 16 percent and 7 percent, respectively., Conclusions: Two milligrams i.v. hydromorphone provides efficacious and rapid pain relief in nonelderly adults presenting to the ED with acute severe pain. However, oxygen desaturation below 95 percent occurred in about one third of patients. Although no noticeable clinical signs of hypoxemia occurred, a conservative interpretation of this finding suggests that 2 mg i.v. hydromorphone is too much opioid to be given routinely to patients in pain as a single initial dose.

Background: Intraspinal drug delivery (IDD) therapy has been increasingly employed in patients with intractable, nonmalignant pain. Before implantation of permanent intraspinal pump, an intraspinal opioid screening trial is conducted to demonstrate the efficacy. The patient-controlled continuous epidural opioid infusion trail, performed in an outpatient setting, is widely accepted by many interventional pain specialists., Objective: To report a case of severe edema observed during the continuous epidural hydromorphone infusion trial., Case Report: An otherwise healthy 68-year-old lady with a 5-year history of severe low back pain and bilateral leg pain because of failed back surgery syndrome was referred to our clinic for IDD therapy. A tunneled lumbar epidural catheter was placed at L2-L3 with catheter tip advanced to L1 under fluoroscopic guidance. Satisfactory catheter placement was confirmed by epidurogram. The catheter was then tunneled subcutaneously and connected to a Microject patient-controlled epidural analgesia (PCEA) pump (Codman, Raynham, MA). The pump was programmed to deliver hydromorphone (0.1 mg/ml) at basal rate of 0.3 ml/h. The bolus dose was 0.1 ml with a 60-minute lockout interval. The patient was instructed how to operate the infusion pump. During the following infusion trial, she reported satisfactory analgesia (> 70 percent pain reduction) and was able to wean off her other systemic opioids. However, she developed diffuse edema and gained over 16 pounds during the 5-day infusion trial. Her edema finally resolved 3-4 days after termination of the epidural infusion., Conclusion: Edema may occur and persist during epidural hydromorphone infusion. This report represents the first case report, to the best of our knowledge, describing severe edema in a patient on continuous epidural hydromorphone administration during an outpatient epidural infusion trial.

Hydromorphone, one of the oldest and most potent of opioids, is an effective alternative to morphine. With a variety of routes of administration, it has an efficacy similar to that of morphine. The FDA has recently approved the first commercially available extended-release formulation, a once-daily hydromorphone for the management of moderate to severe pain in opioid tolerant individuals with an anticipated extended period of use. The formulation exhibits less peak-to-trough fluctuation in plasma concentration, while providing analgesia statistically indistinguishable from its immediate-release counterpart. The manufacturer and the FDA have articulated a plan to minimize unskillful prescribing and abuse/diversion through education, supply-chain integrity, and surveillance. It is anticipated that Palladone will be a valuable addition to the limited armamentarium of extended-release opioids.