ABSTRACT

Oxymorphone extended release is a relatively recent addition to the clinical armamentarium of modified or continuous release opioid analgesics for the treatment of moderate to severe pain. This review provides an overview of published and certain internationally presented study data of efficacy, safety and tolerability.

Introduction

Oxymorphone is a semisynthetic u-opioid agonist. As such, it has properties that exert analgesic efficacy as well as opioid-related side effects [1–4]. Initially, oxymorphone was available in either injectable or suppository formulations. Recently, two additional formulations became available: an immediate release oral pill, and a modified or extended release (ER) tablet, allowing up to 12 hours of pain relief [5,6]. Prior to these recently marketed versions, oxymorphone had been utilized in cancer pain settings as well as obstetric pain. The addition of oral forms has lead to increased interest in oxymorphone clinical applicability.

The intention of this paper is to review published data concerning oxymorphone extended release. Over a dozen controlled and numerous noncontrolled efficacy studies have been published concerning oxymorphone ER. In addition, 2,000 patients have been studied. These studies will be reviewed in the following sections: key efficacy trial data; cancer pain; osteoarthritis (OA) pain; chronic lower back pain; and neuropathic pain. This review will not attempt to review immediate release oxymorphone, nor will it address the pharmacokinetics, metabolism, or risk profile associated with this or other opioid analgesics. Those topics will be discussed elsewhere in this supplement. Special attention will be made to address issues of long-term analgesic efficacy (studies lasting greater than 3 months).

Chronic pain is a significant public health issue, affecting as many as 15–20% of the adult population in the United States. It is among the most frequent reasons cited for seeing a healthcare professional [7]. Treatment remains less than optimal, with as many as 50% of those suffering with chronic pain not achieving satisfactory relief [8]. Among the most frequent causes of chronic pain are cancer-related pain, chronic low back pain, OA, and neuropathic pain. The purpose of this review is to provide an overview of published data on oxymorphone ER in the management of these common causes of chronic pain. Oxymorphone ER (Opana ER) has been approved for the treatment of moderate to severe pain requiring round-the-clock analgesia for an extended period of time [5].

Opioid analgesics are utilized in numerous clinical settings and are among the most prescribed analgesics. Opioids are considered cornerstones of analgesic therapies for cancer pain, postsurgical, and acute pain [9–14]. The management of noncancer pain with opioids remains controversial [8,15–18]. Several recently published controlled trials have documented the efficacy and tolerability of oxymorphone ER in diverse clinical settings in both opioid experienced and opioid naïve populations [19–21]. In addition, analgesic effectiveness appears to be maintained for at least 12 weeks and for as long as 52 weeks in open-label extension trials [22–27]. Oxymorphone ER may therefore be considered as an option in the pharmacologic management of persistent pain requiring opioid analgesics. It has been observed in several trials that oxymorphone ER is well tolerated if titration to effect is done gradually. This matches previously reported findings with other opioids [23,28].

Key Efficacy Trials

Oxymorphone ER has been studied and found to be effective and well tolerated for the management of moderate to severe pain. The pivotal efficacy data that was submitted for approval was developed in two randomized placebo-controlled double-blind studies assessing the safety and efficacy of oxymorphone in the management of moderate to severe chronic lower back pain (CLBP) in both opioid-naïve and opioid-experienced patient populations. These are cited in the product packet insert [5]. A unique factor of the oxymorphone ER efficacy studies was that they were 12 weeks in duration.

Katz et al. evaluated the efficacy of oxymorphone ER in the management of sub-optimally controlled CLBP in opioid naïve patients in a 12-week double-blind, placebo-controlled trial [24]. They found that stabilized doses of oxymorphone were safe and effective over a 12-week treatment period.

The authors utilized an enriched enrollment, randomized withdrawal study design. This methodology included an open-label titration phase where patients were titrated to an optimal analgesic dose with oxymorphone ER. Sixty-three percent of participants were titrated and stabilized within 1 month. For patients completing titration, average pain intensity decreased from 69.4 mm on a visual analog scale (VAS) at screening to 22.7 mm (P < 0.0001). During the titration phase, 18% had to discontinue due to intolerable side effects and 1% from lack of efficacy.

After randomization, patients either remained on oxymorphone ER with oxymorphone for breakthrough/rescue, or placebo and oxymorphone immediate release for rescue. After 4 days, rescue was limited to two doses of immediate release oxymorphone per day. The mean effective dose of oxymorphone ER was 40.05 + 25.8 mg. Sixty-eight percent of oxymorphone patients were able to complete the study vs 47% of placebo patients. Placebo patients discontinued earlier in the study due to lack of efficacy. As would be anticipated, pain scores worsened in the placebo group as compared to the treatment arm. After titration, 97% of stabilized patients rated oxymorphone ER treatment as good, very good, or excellent. At the end of the study, that number diminished somewhat to 81%, whereas the placebo group was rated good, very good, or excellent at 42.2%.

Adverse events (AEs) were class-specific and included constipation, sedation, nausea, and dizziness. During the course of the study, 8% of patients discontinued due to AEs. Over 68% of patients experienced some form of AE during the titration phase, with 33% being mild and 6% being qualified as severe. The incidence was lower after stabilization and entry into the double-blind phase. According to the authors, the low rate of discontinuation after stabilization suggested that opioid-naïve patients gradually acclimated to therapy.

Hale et al. demonstrated safety and efficacy of oxymorphone ER in a 12-week double-blind, randomized placebo-controlled trial in opioid experienced patients with chronic moderate to severe CLBP [25]. Using a similar methodology as described above, oxymorphone ER provided efficacious, long-term analgesia and was generally well tolerated. In this trial, patients were switched from equianalgesic doses to oxymorphone ER using conversion tables previously defined. The mean VAS scores at initiation was 69.5 ± 17 mm at baseline and was reduced to 22.2 ± 10.8 mm at completion of titration. In this trial, those who were studied were titrated to effective doses within 30 days (57%). The mean dose for the active arm after titration was 80.9 ± 59.3 mg; for the placebo group, it was 93.3 ± 61.3 mg. Total daily doses ranged from 20 mg to 260 mg per day. Once the active study began, 70% of active arm patients completed the study, whereas 26% of placebo arm were able to complete. The most frequent reason cited for dropout was AEs (19%).

These authors' findings were similar to the opioid-naïve population discussed above with oxymorphone ER being superior to placebo for the treatment of CLBP. In addition, they reported that pain did not increase, and efficacy was maintained for the 12-week treatment course. The analgesic effect was maintained for 80% of patients during the 12-week study. However, 30% of patients did drop out during this time period, 11% for lack of efficacy when patients were required to maintain study doses. Ten percent dropped out due to treatment-emergent side effects. The authors suggested that this dropout rate was less than that noted in other trials for analgesics. The authors concluded from this study that a majority of opioid-experienced patients with CLBP were successfully converted to and titrated with oxymorphone ER within 1 month to a dose that was effective and well tolerated.

Cancer Pain

Pain associated with cancer remains a significant cause of morbidity and suffering [14]. Advances in treatment have helped improve patients' pain, mitigate suffering, and perhaps offer improvement in quality of life [9]. Opioids are recognized as keystones in the management of moderate to severe pain associated with cancer, by clinicians, specialty societies, and international organizations [9,14].

Oxymorphone ER has been evaluated and shown to be effective in clinical trials of patients suffering with cancer-related pain [19,27,29]. In addition, it may offer an option in certain types of cancer-related pain syndromes such as persistent neuropathic pain [10,27]. Finally, the availability of oxymorphone in a number of formulations, including injectable, oral, and rectal, makes it a valuable addition to the clinical armamentarium [2,3,10].

In a study by Gabrail et al., the analgesic efficacy of oxymorphone ER was compared to oxycodone continuous release (CR) [29]. The study was a randomized, double-blind, two-period crossover study with adult patients with moderate to severe cancer-related pain, requiring long-term outpatient treatment with opioids. An open-label titration phase, with either oxymorphone or oxycodone CR, was carried out to determine a stable analgesic dose. This was defined as analgesia requiring no more than two rescue doses of medication 2 days in a row, and associated with tolerable side effects. This was done to calculate equianalgesic dosages for the double-blind phase of the trial, at a conversion rate of oxycodone 2:1. It also is in line with previously published findings [12,13]. Once entered into the treatment phase, patients were randomized into oxycodone CR or oxymorphone ER arms. Efficacy was assessed with the Brief Pain Inventory, global evaluations of patients and physician satisfaction on treatment, and the Karnofsky Performance Status (a functional assessment tool validated in cancer populations). Of the 45 patients randomized, 37 comprised the efficacy evaluable population and 5 subjects withdrew during the double-blind treatment period. No patient discontinued due to lack of efficacy. Rather, AEs unrelated to the study drug and consent withdrawals were cited as reasons for dropout.

The mean analgesic doses were 91.9 mg for oxycodone CR and 45.9 mg for oxymorphone ER. There were no significant differences in any analgesic outcome data between the study arms. In addition, Karnofsky scores reflecting functional status were comparable. Patient and physician global satisfaction scores for both arms were rated quite well. Rescue medication use was low in both groups. This study demonstrated the relative equivalence of oxymorphone and oxycodone, where oxymorphone ER was found to have an equianalgesic dose of 2:1. The total incidence of AEs was similar between both groups, and according to the authors, was within the acceptable ranges for this patient population.

Sloan et al. conducted a pilot study assessing the safety and effectiveness of oxymorphone ER for the treatment of cancer-related pain [19]. The authors reported oxymorphone ER to be easily titrated and well tolerated. Patients with a variety of cancer types suffering with moderate to severe pain, who had been previously stabilized on either morphine CR or oxycodone CR, were eligible. Patients could be rapidly and safely converted to oxymorphone ER, often at lower milligram doses with no decrease in analgesic effectiveness or increase in reported adverse effects. This trial consisted of a multicenter, prospective, multidose open-label sequential crossover study. Eligible patients were enrolled if they were opioid tolerant, with cancer-related pain requiring at least 20 mg of oxycodone or equivalent for analgesia. Patients were initially stabilized on either morphine CR or oxycodone CR. Those who were able to attain adequate analgesia for >3 days were entered into the study. Following 7 days at a stable dose, patients were then crossed over and received treatment with oxymorphone ER. Fifty-nine of 63 patients were able to be rapidly and successfully switched to oxymorphone ER (93.7%). There were no observed changes or differences noted in measured pain scores or reported side effects. Patients required more rescue medication use in the morphine subgroup than either the oxycodone or oxymorphone groups.

Slatkin et al. demonstrated that Oxymorphone ER can be safe and effective in cancer patients with chronic pain requiring opioid analgesics when used long term [27]. The authors observed that pain scores and opioid doses were stable throughout the study period of 52 weeks, while being maintained by a median dose of 110 mg/day with minimal need for rescue doses. Patients were drawn from a previous population studied for analgesic efficacy of oxymorphone [19]. Patients evaluated completed a 52-week course. Thirty-six percent of patients were able to complete the study. Primary reasons for discontinuations included insufficient therapeutic effect (11.4%), serious AEs (20.5%), poor compliance with protocol (9.1%), and patient requested withdrawal (11.4%). In those participants who remained in the study, effectiveness was maintained with the same degree of pain relief based on VAS scores. More than 90% of patients rated the study medication from good to excellent. Over the course of the study, typical opioid side effects were observed.

Arthritis-Related Pain

Pain and resultant impairment in quality of life resulting from OA affects more than 20 million Americans [30]. Treatment guidelines advocate a multidisciplinary approach [30,31]. Opioids are recognized as a treatment option for patients with moderate to severe pain [8,15–17]. Oxymorphone ER has been shown to be effective in short-term and long-term open-label trials in the management of OA pain [21,22,26]. Below is a review of these recent data.

Matsumoto et al. studied oxymorphone ER in a randomized, double-blind placebo- and active-controlled study [22]. The study population was made up of individuals who had completed a previous double-blind placebo and active-controlled trial with oxymorphone ER. Patients were considered eligible for the initial study if they had pain requiring nonsteroidal anti-inflammatory (NSAID), acetaminophen, or an opioid in the 75–90 days before the screening period for the study, and analgesic response to these agents must have been deemed suboptimal.

In this trial, patients were randomized to oxymorphone ER 20 mg or 40 mg; oxycodone CR 20 mg; or placebo, dosed every 12 hours. The primary efficacy was measured in reduction in VAS scores. Secondary endpoints included measuring improvement with functional assessment tools (Western Ontario McMasters Osteoarthritis Index [WOMAC] and Short Form-36 (SF-36)). Four hundred and ninety-one patients were randomized with 269 patients completing the study. Primary reason for withdrawal given in the active group was nonserious side effects (nausea, dizziness, and constipation). In the placebo group, dropout was attributed to lack of efficacy. The primary efficacy end point was a change from baseline pain reports in weeks 3 and 4 vs placebo for both strengths of oxymorphone group. The oxymorphone group improved from baseline on WOMAC as well as pain and functional subscores in SF-36. Oxycodone in this trial failed to achieve statistical improvement in pain. This may be due to the dose chosen as opposed to an inherent lack of effect. The dose chosen was not equianalgesic. In fact, based on accepted equianalgesic table (oxymorphone with twice potency), the oxycodone dose was significantly less than the study doses of oxymorphone. Safety evaluation found a significant number of AEs in all active study groups. Eighty-three percent of all patients experienced at least one AE. Most of these were assessed to be mild to moderate in severity and are typical for opioid therapy. The oxymorphone subgroups had significantly higher incidence of nausea, vomiting, and pruritis, and clinically lower incidence of headaches compared to oxycodone. Again, this result, excluding the lower incidence of headaches, is also attributable to the higher relative dose of oxymorphone as compared to oxycodone.

Kivitz et al. carried out a 2-week randomized double-blind placebo-controlled dose-ranging study comparing the efficacy of oxymorphone ER and placebo in adults with OA of the hip or knee [21]. Patients were eligible if they were taking opioids or were deemed to require opioids to manage pain associated with arthritis of hip or knee. Following a 7-day washout, and if pain scores were greater than 40 mm on a 0–100 mm VAS score, patients were randomized to one of four arms, including one placebo group and three others where oxymorphone was dosed at between 10 and 50 mg given every 12 hours (BID). Outcomes were determined according to pain response, functional assessments including WOMAC and SF-36, Chronic Pain Sleep Inventory score, and AEs. Three hundred and seventy patients were randomized: 95 received oxymorphone ER 10 mg, 93 received oxymorphone 40 mg, and 91 subjects received 50 mg. Ninety-one subjects were enrolled in the placebo group. One hundred and ninety-eight patients completed the study. All oxymorphone ER groups were superior to placebo in the VAS measure. There was a dose-dependent response, with the 50 mg allowing for greatest reduction in pain. The 10 mg dose, however, failed to meet the primary VAS end point compared to placebo, though according to the authors, “… the improvements in pain observed with each dose of oxymorphone ER exceeded the established criterion for clinically meaningful pain relief-a change of >1.5 mm on a VAS.” In addition, the 40 and 50 mg groups also showed functional improvements as measured by the SF-36 and WOMAC. Again, the authors described that a less robust response was seen in the 10 mg dosage.

AEs were those typically associated with opioids. Due to AEs, 25.3% of participants withdrew, with the higher doses of oxymorphone seeing considerably greater percentage of withdrawal (>50% for the 40 and 50 mg groups) compared to either the lower dose of active drug (25%) or placebo (9.9%). Nausea and vomiting were the most frequent AEs observed. The corollary is that there was a three-fold increase in the number of withdrawals due to ineffectiveness in the placebo group compared to the active groups. The author's conclusions were that the 40 and 50 mg oxymorphone ER groups saw greater analgesic efficacy with concomitant functional improvement, though the 10 mg did provide significant efficacy in terms of certain aspects of the WOMAC and the SF-36.

McIlwain and Ahdieh carried out a 1-year study assessing safety, tolerability, and effectiveness of oxymorphone ER for moderate to severe pain from OA [26]. The study population was made up of individuals who had completed a previous double-blind placebo and active-controlled trial with oxymorphone ER. Patients were considered eligible for the initial study if they reported pain requiring NSAID, acetaminophen, or an opioid in the 75–90 days before the screening period for the study, and response to these agents must have been deemed suboptimal. Efficacy was monitored with several analgesic measures (5 points and 100 mm VAS), pain recall scores (0–100 VAS), and patient global assessment of effectiveness (5-point categorical scale). In addition, AEs were monitored, including nausea and drowsiness. Assessment was done at weeks 1, 2, 6, and 10, then every 6 weeks thereafter. Participants were allowed to use nonopioid analgesic and concomitant medications.

One hundred and fifty-three subjects were enrolled. Patients who were on the placebo arm were considered opioid naïve. These patients were generally started at oxymorphone ER 20 mg BID, though investigators could use discretion at determining initial dose. Otherwise, patients were maintained on their existing dose from the prior study. Sixty-one percent of patients completed the study. The most common reason for withdrawal was the occurrence of nonserious AEs (N = 49), the most often cited being typical opioid side effects. Of those who dropped out due to side effects, 47% were in the placebo arm of the original study. Among the remainder of patients, the dropout rate for AEs was half the naïve group's rate. Interestingly, the authors observed that nausea scores peaked at the end of week 1 and were not clinically significant. After week 6, theses scores dropped below baseline. Similarly, drowsiness scores were low at baseline then showed transient increases in a nonsignificant manner over the next several weeks.

Effectiveness was observed throughout the course of the study. Some patients (7.8%) dropped out due to lack of effect. The placebo arm group entered with the highest baseline pain scores, saw the greatest drop in pain scores, and these decreases remained stable throughout. Mean baseline pain scores decreased from 51.2 mm to 19.2 mm at week 52. Patient global assessment of study medication noted that at least 80% of patients rated oxymorphone ER as good to excellent at each scheduled visit. The median average daily dose of oxymorphone ER was 40 mg throughout the study, and the mean values were 48 mg at week 1 and 62 mg at week 52. The primary reason cited by the authors for the change in mean daily dosing was due to the disproportionate withdrawal of opioid-naïve patients entering the study at 40 mg/day. This group had a high dropout percentage as previously noted. The authors believed that the data did not provide any clinical evidence of analgesic tolerance to oxymorphone ER. The authors concluded that this 1-year open-label study demonstrated that oxymorphone ER was safe and effective for the relief of moderate to severe pain due to OA. Additionally, they proposed that the study drug maintained a stable reduction in pain intensity with stable dosing. Finally, they noted that oxymorphone was favorably assessed by 80% of those who completed the study.

Guay has pointed out that oxymorphone appears to be effective and well tolerated in the elderly and that there were no overt reasons that it should not be used in the elderly [4]. This observation was based on certain pharmacologic properties of the molecule, including its metabolism. OA is primarily a disease of the elderly with a very high preponderance in individuals greater than 50 years in age. In addition, as patients age, the complexities of drug regimens increase. The lack of cytochrome P 450 enzyme (CYP 450) activity may make oxymorphone a more attractive molecule in those patients requiring drugs metabolized through the liver [1,2,32].

Lower Back Pain

CLBP is among the most frequent causes of pain seen in primary care and pain centers [17,33,34]. It is a major cause of morbidity, lost productivity, and medically related disability. Treatment is generally multidisciplinary, including interventional therapies, medical management, psychosocial therapies, and rehabilitation. Opioids may be effective, particularly in the short term in the management of CLBP, with most studies suggesting improvement in pain and that these results suggest superior efficacy compared to placebo [17]. The risks of long-term opioid use in such patients must be balanced against potential common adverse effects, the development of impaired function, and the manifestation of misuse and abuse [15,16].

Hale et al. [20] conducted a multicenter randomized double-blind placebo-controlled study looking at the efficacy and safety of ER oxymorphone with both placebo and active control; in this case, oxycodone CR. The patients were seen in an outpatient setting, with moderate to severe lower back pain, and required opioid analgesics. The study initially titrated patients to effective analgesic doses of either oxymorphone ER or oxycodone CR. Those who realized appropriate analgesia were then randomized into the double-blind treatment phase and either received placebo or continued on active therapy. Both active arms were superior to placebo. Doses remained stable during the study period for both oxymorphone ER and for oxycodone CR. The oxymorphone and oxycodone groups required a significantly lower amount of rescue medicine as compared to placebo. AEs were similar. The effective analgesic dose for oxymorphone ER (79.4 mg/day) was approximately one-half that of oxycodone CR (155 mg/day), though the total rescue dose was approximately the same (25.5 mg morphine sulfate vs 24.4 mg morphine sulfate; P = 0.24.) Among outcome measures, improvement was observed in a number of domains within the Brief Pain Inventory; among them were improvements in general activity, walking ability, normal work, mood relations with other people, sleep, and enjoyment of life. The overall incidence of side effects was essentially equal between study drugs. Oxymorphone did have a higher incidence of constipation (35% vs 29%).

In a subsequent study of opioid-naïve patients suffering with diverse pain types, including CLBP, Rauk et al. noted similar findings in patients with more diverse pain condition among opioid naïve patients [23]. They summarized their findings by noting that oxymorphone ER provided effective analgesic relief from moderate to severe pain in opioid-naïve patients. The authors suggested that gradual or slower titration was well tolerated with a low rate of discontinuation.

Neuropathic Pain

Neuropathic pain (NP) is defined as pain resulting from disease or injury arising from the nervous system [33]. Treatment is difficult and often requires multimodal approaches for best possible outcomes. A number of agents have been demonstrated to improve pain and function in neuropathic pain, including opioids [35–38]. In these studies, various opioids were shown to be superior to placebo in randomized placebo-controlled clinical trials. In addition, opioids in combination with certain adjuvants have been shown to be superior to either adjuvant or opioid given alone, suggesting pharmacologic synergy [39].

There are few published data on oxymorphone in NP [40]. However, as has been shown, its analgesic efficacy has been consistently demonstrated in other clinical states [19–29]. There does not appear to be any pharmacologic reason why oxymorphone ER should be devoid of analgesic properties in this condition.

Slatkin et al. presented data on the efficacy of oxymorphone ER in NP associated with cancer [41]. Eligible patients were identified from a previous controlled study of cancer patients with chronic pain. Participants were adults with moderate to severe chronic cancer pain diagnosed as neuropathic. Mixed-pain patients were excluded. Patients were eligible if their opioid requirements were ≥20 mg of oxycodone or the analgesic equivalent of ≥30 mg of oral morphine who attained stable analgesia of the titrated study drug for ≥3 days, defined as ≤3 rescue doses of opioid/day. The study design was prospective, multidose, open-label, sequential crossover study. Patients were stabilized with dose titration of morphine sulphate CR or oxycodone and then treated for 7 days. They were then crossed over to oxymorphone ER q 12 h at an estimated equianalgesic dose and treated for 7 days. Rescue with immediate release opioid formulation at doses of approximately 10% of the total daily dose of study medication. Effectiveness was assessed at the end of titration, following the first 7 days of treatment with either morphine or oxycodone CR, and then following the second 7-day treatment period with oxymorphone ER. Patients were assessed for their least, worst, and average pain during the previous 2 days prior to switching agents. Eleven patients in the trial were identified as having neuropathic pain. Nine individuals completed the first treatment and 8 subjects completed the oxymorphone phase. Of those going on to oxymorphone phase, 4 received oxycodone CR, and 4 were given morphine CR. At study initiation, despite being on opioids at time of enrollment, mean VAS score was >70 mm. After the first 7-day period, morphine and oxycodone mean average pain VAS scores were 29 mm. For oxymorphone ER, it was 24 mm. Seven of eight patients experienced at least one AE. The authors note that all but one AE were mild to moderate, and typical for AEs seen with opioid analgesics. One patient withdrew during the oxymorphone phase due to somnolence and pain.

Prager et al. reported the interim results of an open-label long-term study of safety and effectiveness of oxymorphone ER in moderate to severe neuropathic pain [40]. Patients were eligible if they were adults, with a diagnosis of chronic moderate to severe NP of >3 months duration who experienced treatment failure with one or more analgesic agents, including opioids used to treat neuropathic pain, and had a pain intensity of 4 or greater on a 0–10-point scale using the Brief Pain Inventory. Subtypes of NP included postherpetic neuralgia, diabetic neuropathy, complex regional pain syndrome, human immunovirus neuropathy, idiopathic sensory neuropathy, traumatic neuropathy, central neuropathy, or other peripheral neuropathies. Patients were excluded if they had asthma, substance abuse histories, or other contraindications to opioid therapy.

An initial phase included dose titration and stabilization, followed by a 12-month long-term maintenance phase. Patients were converted to oxymorphone ER if they were already on another opioid or, if opioid naïve, started at 5 mg BID for 2 days. Thereafter, all patients were titrated to a stable and effective dose of oxymorphone ER, as measured by a reduction in average daily pain scores to ≤4 for at least 3 of 5 consecutive days. Once stabilized, patients were entered to the maintenance phase. If adequate analgesia could not be achieved after 28 days, reassessment for appropriateness was carried out. Once in the maintenance phase, oxymorphone immediate release (5 mg and 10 mg) was available.

At the time of reporting, only limited data were available. Of 120 patients enrolled, 64 completed the titration/stabilization phase and 14 were still in titration. The authors observed that the mean effective analgesic doses that were determined during the titration phase differed depending on the time it took to obtain adequate analgesia. The mean analgesic dose was found to be 59.64 mg of oxymorphone ER if titration was successful in less than 14 days. If titration took between 15 and 21 days, the mean effective analgesic dose was 60 mg. For those who required 22–28 days, the mean effective analgesic dose was 101.15 mg of oxymorphone ER. The dose ranges for the entire study population were remarkable, ranging from 10 mg to over 200 mg of oxymorphone ER per day. Forty-two patients withdrew during titration. AEs were identified as the cause of withdrawal in one-half of the group. The authors noted that drug-related AEs prevented titration to benchmark analgesia levels, and were effectively a dose-limiting phenomenon. In other trials of opioids in neuropathic pain, dose-limiting side effects are also reported. In addition, the aggressive titration phase may not have been conducive to patient tolerability as discussed previously [23].

Conclusion

Oxymorphone ER has been studied in a number of cancer and noncancer pain states. Over 2,000 patients have participated in 12 clinical trials. It has been shown to provide analgesia that is well tolerated and associated with comparable side effects to other opioids. The key efficacy trials reviewed by the Food and Drug Administration were unique in their length, and showed stable continuous analgesia for the 12-week study course. Recent reviews of oxymorphone have concluded that as an analgesic, its effectiveness, safety, tolerability, and documented viability as an analgesic over year-long studies may make it a valuable addition to the pain management armamentarium for cancer- and noncancer-related disease states [9,18,42–44].

Several key points may be safely gleaned from reviewing these data. These include the following:

  1. Rapid titration to relatively high doses or fixed dose studies was associated with poor tolerability and was thus associated with relatively high dropout rates due to AEs when compared to placebo. In those circumstances, oxymorphone ER-related dropout rates were moderately high, though comparable to extant literature of opioid clinical trial data. However, subsequent data with more gradual titration found better tolerability when compared to either rapid titration or to fixed dose approaches. This suggests that the clinical maxim of “start low and go slow” may be relevant and help diminish the incidence of poor tolerability. This is in concern with other published experience with potent opioids.

  2. In addition, several open-label extensions have been published, noting that oxymorphone ER was able to maintain analgesic effect over a relatively prolonged period of time (up to 52 weeks) with remarkable dose stability. These findings may suggest but certainly do not prove the maintenance of long-term effects. In one study, the authors suggest that tolerance was not a significant clinical issue. Further studies will be needed to bear this out as clinically relevant or significant.

  3. Oxymorphone ER was associated with consistent analgesia and was associated with high degrees of patient satisfaction.

Disclosure

The author declares no conflict of interest.

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