4.1 Opioids for Pain Control

Opioids are highly important and effective analgesics when dealing with pain, whether it be acute or chronic. Because these drugs have many side effects and a high abuse potential, all healthcare providers who consider prescribing an opioid analgesic for a patient must first undertake a risk-versus-benefit analysis that takes into account the patient’s other medications, medical and psychological status, and pain level at a minimum. For example, when you perform a minor surgical treatment on a patient (e.g., tooth extraction) the choices for a postsurgical pain control medication include nonopioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioid medications. The two most commonly used opioid drugs in this situation are codeine and hydrocodone, which are usually dispensed in combination with ibuprofen or acetaminophen. These opioids are categorized as moderate-strength analgesics and they are categorized by the US Food and Drug Administration (FDA) as Schedule III drugs, which means they are less dangerous than the more potent, Schedule II opioids (e.g., morphine, oxycodone, fentanyl, hydromorphone, oxymorphone, methadone). Many consider codeine or hydrocodone to be the first-line treatment for management of acute pain due to postsurgical and post-traumatic injury. The vast majority of acute traumatic or procedural pain is mild to moderate pain; selecting an opioid medication as the first choice for analgesia is not an evidence-based clinical practice. Most experts recommend that a Schedule II or III opioid is appropriate postsurgically only when a patient has severe postsurgical pain that a nonopioid or an NSAID does not relieve.

The two main concerns regarding the appropriate use of any medication are its efficacy and its adverse-effect profile. For example, NSAIDs produce gastritis, and acetaminophen can induce liver toxicity; for some patients, this shifts the balance of risk-to-benefit in the favor of opioids and in particular the noncombination-drug opioids.¹ Added to these two concerns is a third issue, namely, the inappropriate use of a prescription medication. In the last decade, prescription drug abuse, mainly of opioid prescriptions, has become a growing problem for law enforcement and regulatory officials, based on a pattern of “overprescribing” opioids.² Annual surveys about drug use in household and school populations clearly show that there is a rapidly rising rate of prescription drug misuse and abuse.³ These considerations and other factors that influence analgesic choice are described in this chapter.

4.1.A Schedule III Opioids

The drugs that are categorized as Schedule III by US law are considered to have the following characteristics: (1) a potential for abuse that is less than the drugs or other substances in Schedules I and II; (2) a currently accepted medical use in treatment in the United States; and (3) the potential that abuse may lead to moderate or low physical dependence or high psychological dependence.⁴ In this group of drugs are two of the most commonly prescribed opioids: codeine and hydrocodone. Both are commonly used by physicians and dentists after a surgical procedure and for other spontaneous pain disorders and will be reviewed next. One opioid that is actually listed by the FDA as a Schedule IV analgesic for mild pain that is not be reviewed here is propoxyphene. The reason for its exclusion is that in 2009 the FDA added a “black box” warning to the labeling that comes with this drug to reflect the risk of overdose⁵: “Propoxyphene should be used with extreme caution, if at all, in patients who have a history of substance/drug/alcohol abuse, depression with suicidal tendency, or who already take medications that cause drowsiness (e.g., antidepressants, muscle relaxants, pain relievers, sedatives, tranquilizers). Fatalities have occurred in such patients when propoxyphene was misused.” Finally, the analgesic agent tramadol, which does binds to opioid receptors but is not listed by the FDA as an opioid nor has it been given a schedule rating, is covered in Chapter 3.

Hydrocodone

Indications

Hydrocodone is an opioid with moderate potency indicated for moderate to severe pain. It is always combined with either a nonopioid analgesic or a nonsteroidal anti-inflammatory medication. Combination therapy is widely used for the clinical management of acute pain based on the principle that combining two drugs with different mechanisms of action provides additive analgesic effects while reducing the risk for adverse effects.

Dosage

Hydrocodone comes as a tablet, a capsule, a syrup, a solution (clear liquid), an extended-release (long-acting) capsule, and an extended-release (long-acting) suspension (liquid) to take by mouth. The tablet, capsule, syrup, and solution are usually taken every 4–6 hours as needed. The extended-release capsule and the extended-release suspension are usually taken every 12 hours as needed. There is no maximum (ceiling) dose for any of the pure opioid agonists since tolerance makes an individual progressively immune to the effects of these medications; however, maximum doses are determined by the inclusion of acetaminophen or ibuprofen with the hydrocodone. The usually prescribed dose of hydrocodone combined with either acetaminophen or ibuprofen is 5 or 7.5 mg and the typical dosing is four times a day.

Adverse Effects

The side effects of the various opioids are qualitatively similar and are discussed under “Opioid side effects” (Sec. 4.1.C). If a unique side effect is associated with a specific formulation, this is discussed in the section dedicated to that particular opioid. Hydrocodone is not used as a stand-alone medication but is combined with either acetaminophen or ibuprofen; the unique side effects of each combination are typically related to the nonopioid analgesic in the combination and these side effects are discussed in detail in Chapter 3.

Efficacy for Acute Pain

A 2005 study compared the efficacy and tolerability of various combinations of opioids and nonopioid or NSAID analgesics (oxycodone 5 mg/ibuprofen 400 mg vs. oxycodone 5 mg/acetaminophen 325 mg and vs. hydrocodone 7.5 mg/acetaminophen 500 mg) versus a placebo in a dental pain model on 249 patients.⁶ This was a multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group, single-dose study in patients experiencing moderate to severe pain after surgical removal of at least two ipsilateral impacted third molars. The authors reported that oxycodone 5 mg combined with ibuprofen 400 mg provided significantly greater analgesia when compared with oxycodone 5 mg combined with acetaminophen 325 mg. Oxycodone also had greater efficacy than hydrocodone 7.5 mg combined with acetaminophen 500 mg or the placebo medication. The lowest frequency of nausea and vomiting occurred in the groups that received oxycodone 5 mg/ibuprofen 400 mg (6.5% and 3.2%, respectively) and placebo (3.2% and 1.6%). They concluded that in patients with moderate to severe pain after surgery to remove impacted third molars, oxycodone 5 mg/ibuprofen 400 mg provided significantly better analgesia throughout the 6-hour study compared with the other opioid/nonopioid combinations tested, and it was associated with fewer adverse events. However, the results of this study must be weighed against the previously mentioned national epidemic of prescription drug abuse occurring in the United States. In addition, while adding an opioid to ibuprofen will make the combination more effective and in some cases is justified, for most dental procedures this is not justified. A clinical study evaluating the therapeutic benefits of this drug combination suggested that adding the opioid would result in a marginal additive analgesic effect in combination with 400 mg of ibuprofen alone, but with a greater incidence of side effects than use of the NSAID alone.⁷

Efficacy for Chronic Pain

Short-acting (also called immediate-release) opioids are not suggested for management of chronic pain, based on the conventional wisdom that prescription drug abuse is less likely in longer acting (also called extended-release) opioids because the peak serum levels are lower and therefore less likely to induce euphoric effects. A recent study compared patient responses to a longer acting opioid (extended-release morphine) with responses to a shorter acting opioid (hydrocodone plus acetaminophen) and placebo in a randomized, double-blind crossover study using markers of abuse liability.⁸ Patients indicated their craving for drugs on visual analog scales (VASs) and completed the Addiction Research Inventory (ARI) scale questionnaire. The results in this study suggested that differences in the ARI scores were statistically significant between groups but were judged by the authors of the study to be clinically unimportant. They concluded, in contrast to conventional wisdom, that long-acting opioids do not have a substantially lower abuse potential than do short-acting opioids or placebo.

A study that compared the effectiveness of two combination-drug formulations showed that hydrocodone 7.5 mg combined with ibuprofen 200 mg was more effective than codeine 30 mg combined with acetaminophen 300 mg.⁹ Another study with mixed chronic pain patients compared oxycodone 5 mg and acetaminophen 325 mg taken four times per day for at least 6 weeks.¹⁰ The neuropathic pain subjects also were taking gabapentin up to a daily dose of 2400 mg. The osteoarthritic patient group reported 64.3% of patients showed improvements in pain symptoms after 15 days of treatment. The neuropathic group reported that 83.3% of patients showed improvement; however, these patients did not have as great a reduction in hyperalgesia and more of the neuropathic pain subjects dropped out of the study than did those in the osteoarthritis group (37.1% vs. 58.3% respectively). The authors concluded that low-dose oxycodone/acetaminophen improved pain symptoms in the majority of the drug-compliant patients.

Codeine

Indications

Codeine is another Schedule III opioid with lower potency used mostly for moderate to severe postoperative pain or acute pain disorders. Codeine is a prodrug, which means it is not an active drug until it has been metabolized by the liver. The primary active compounds of this metabolism are morphine and codeine-6-glucuronide.^11,12 Roughly 5–10% of codeine will be converted to morphine, with the remainder either free or conjugated to form codeine-6-glucuronide (approximately 70%). This metabolism is performed by the P450 cytochrome (CYP) enzymes that are in the liver, especially the CYP-2d6 isoenzyme.

Dosage

Acetaminophen with codeine is commonly used for acute pain and can be taken as frequently as every four hours (q4h) as needed for pain (up to a maximum dose of 360 mg) in opioid-naïve patients. Those patients who are using opioids daily will most likely need and can have a larger dose. The biggest problem with giving a patient more acetaminophen and codeine is the maximum daily dose for acetaminophen is 4000 mg of acetaminophen per day. The common com­binations of codeine and acetaminophen are 300 mg of acetaminophen combined with a variable dose of codeine phosphate usually designated by a number (No. 2 has 15 mg of codeine phosphate; No. 3, 30 mg; No. 4, 60 mg).

Adverse Effects

Like all opioids, codeine, even though it is a lower potency opioid, can produce physical and psychological dependence. Conventional wisdom holds that the withdrawal symptoms for codeine are relatively mild compared with the other opioids. Codeine is like many opioids that can cause a drug–drug interaction with other prescription drugs. The most concerning are those that interfere with CYP-2d6 metabolism such as the serotonin selective reuptake inhibitors (SSRIs), with the exception of (sertraline) Zoloft. The most potent inhibitor is paroxetine (Paxil), followed by fluoxetine (Prozac). In fact, taking a concurrent SSRI and a codeine-containing analgesic will produce an increase in serotonin, risking a dangerous serotonin syndrome adverse reaction.¹³ Sometimes the result of this inhibition is that patients taking codeine postoperatively will take several tablets to relive their pain and the problem this causes is they are at risk of consuming a toxic, liver-damaging dose of acetaminophen.¹⁴ If the drug-to-drug interaction can be predicted and codeine is still the analgesic choice, a reasonable work-around strategy is to suggest that the patient take a holiday from using the SSRI medication well before a planned procedure, based on the length of the half-life of the SSRI or other CYP-2d6 inhibitor being used. Finally, as mentioned, the conversion of codeine into an active analgesic requires the CYP-2d6 liver enzyme. This enzyme may be missing in some individuals due to a genetic polymorphism (about 7% of the Caucasian population). Individuals who inherited a CYP-2d6 deficiency will get many of the adverse effects associated with codeine but little analgesia or euphoria because it is not metabolized.

Efficacy for Acute Pain

A Cochrane review examined whether combining analgesic drugs from different classes with different modes of action improves the efficacy and tolerability or allows a lower dose of each drug than is achieved using the same drugs independently.¹⁵ Specifically the review examined the efficacy of a single-dose oral acetaminophen plus codeine in treating acute postoperative pain and any associated adverse events based on 26 studies with 2295 participants. The review’s results suggested that adverse events were mainly mild to moderate in severity and that incidence did not differ between groups. Moreover, combining acetaminophen with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with less than 20% seen with the placebo. A clinical trial evaluating the combination of a single dose of 400 mg ibuprofen plus 60 mg codeine compared with each drug alone and placebo demonstrated that the ibuprofen-plus-codeine combination resulted in slightly higher mean hourly analgesic scores and produced substantially greater analgesia than codeine 60 mg, but the combination did not produce significantly greater analgesia than ibuprofen 400 mg alone.¹⁶ Comparison of ibuprofen 400 mg plus codeine 60 mg versus ibuprofen 400 mg in another study demonstrated significant differences on several, but not all, derived measures of analgesic activity.¹⁷ Side effects were more frequent following the opioid-containing combination but consisted of minor adverse events such as drowsiness and “faintness.” McQuay demonstrated a 30% increase in analgesic effect with the addition of 20 mg codeine to 400 mg ibuprofen in a crossover study with two doses of the drugs being evaluated.¹⁸ With this lower dose of codeine, no tendency for greater incidence of adverse effects was detected and greater than 70% of subjects expressed a preference for the combination. These and other similar studies provide a basis for adding codeine to a 400-mg dose of ibuprofen as needed to produce additive analgesia but with a dose-related increase in side effects. A minimum dose of 20–30 mg of codeine is needed in combination with 400 mg ibuprofen to produce detectable additive analgesia with minimal side effects. Administration of a traditional dose of 60 mg codeine will usually produce additive analgesia, but for relatively short duration (1–2 hours), compared with the usual duration of ibuprofen (4–6 hours) while producing a significant increase in the incidence of side effects. In the absence of a marketed fixed-dose combination, it may be more practical to initiate analgesic treatment with 400–600 mg ibuprofen on a fixed schedule and dispense 30-mg tablets of codeine to be taken as needed for pain not adequately controlled by the NSAID. This strategy will result in exposure to the opioid for only those patients in need of additional pain relief, thus resulting in a more favorable therapeutic ratio than exposing all patients to opioid side effects. Prescribing codeine as a single entity, that is, not in a fixed combination with another drug, requires careful adherence to regulations associated with Schedule II opioids.

Efficacy for Chronic Pain

Codeine combinations are not recommended for chronic pain for various reasons. First, the population has a high prevalence of polymorphisms that interfere with codeine metabolism. Second, the medication has a higher prevalence of nausea than many other opioids¹⁹ and many patients claim to have had a prior adverse reaction to it. Third, while there is some research⁸ that disputes the convention of using extended-release preferentially over immediate-release opioids, this conclusion is not widely held by experts in the field and needs additional verification.

4.1.B Schedule II Opioids

When pain is severe and Schedule II opioids (e.g., morphine, oxycodone, fentanyl, hydromorphone, oxymorphone, and methadone) are indicated, the liabilities of these medications become a concern. Schedule II drugs have the following characteristics: (1) a potential for abuse that is less than the drugs or other substances in Schedule I; (2) a currently accepted medical use in treatment in the United States; and (3) the potential that abuse may lead to moderate or low physical dependence or high psychological dependence. Opioid adverse effects include nausea, constipation, dizziness, sedation, respiratory depression, dependency, and abuse. These adverse reactions often cause dentists to shy away from Schedule II opioids for analgesic control of orofacial pain, and without specific training and knowledge this caution is probably appropriate. In addition, Schedule II opioids are often not prescribed for fear of regulatory investigation and patients developing dependence on these medications. Fortunately, the current literature suggests that drug dependence is not a problem with opioid use in acute pain.²⁰ The use of Schedule II and III opioids on a longer term basis (for chronic nonmalignant pain) is discussed in Section 4.2.

Morphine

Indications

Morphine is considered the standard opioid and is often the drug of first choice in the treatment of moderate-to-severe cancer and noncancer pain.^21,22 Normally, morphine is titrated to maximum tolerability before moving on to another opioid such as oxycodone, fentanyl, hydromorphone, oxymorphone, or methadone. Morphine is available in a variety of formulations (parenteral, oral, rectal) and the oral form is available in a range of preparations, from immediate release to sustained release, allowing it to be better titrated to the patient’s response.

Dosage

The immediate-release oral formulation of morphine is recommended initially due to its ease of administration and convenience of use. The generic form comes in 15- and 30-mg immediate-release (IR) tablets as well as 15-, 30-, 60-, 100, and 200-mg extended-release (ER) tablets. Most experts recommend switching from an immediate-release morphine sulfate formulation once an acceptable dose is established, to a controlled-release form so that the blood levels of the medication are more stable. A typical regimen consists of a extended-release preparation given every 8–12 hours with breakthrough doses of immediate-release form given every 3–4 hours in between if needed. As a guide, the cumulative as-needed doses should not exceed the total dose given as a sustained preparation for that interval. For example, a patient requiring morphine 120 mg ER every 12 hours should receive morphine 30 mg IR every 3 hours, as needed for breakthrough pain. Regimens will require frequent adjustments, allowing 3–7 days for the patient to respond before initiating a change unless toxicity is apparent. Should a patient fail morphine therapy, another opioid should be instituted and dosed according to its morphine equivalency. Initial dosing of the new opioid should be 25–50% less than the expected equivalent dose of morphine since the patient may not be fully cross-tolerant to the new agent. Cross-tolerance can be seen particularly when changing from a more potent to a less potent agent and is a result of variable effects of each opioid on the opioid receptors.

Adverse Effects

See “Opioid side effects” (Sec. 4.1.C) for information on the adverse effects of morphine.

Efficacy for Acute Pain

Morphine is FDA approved and an effective pain reliever, but it is not generally indicated as a first-line option for pain in the postoperative period for outpatients or for nonextensive acute traumatic pain. The logical approach—and the approach recommended by the World Health Organization (WHO)—for acute pain management is to use nonopioid analgesics first, medium-potency opioids second, and then and only then consider highly potent opioids such as morphine or any of the other Schedule II opioids (see Table 4.1).²³ The ultimate choice of the analgesic is the treating clinician’s decision and should be based on the nature of the traumatic injury and the extent of the surgical procedure performed.

Table 4.1 Choosing a medication for pain management

COX-2, cyclooxygenase-2; NSAID, nonsteroidal anti-inflammatory drug.

Efficacy for Chronic Pain

There have been several recent studies that have examined and demonstrated excellent efficacy of extended-release morphine sulfate tablets as a treatment for chronic pain.^24,25 An international expert panel reviewing evidence regarding the role of highly potent opioids in the management of chronic severe pain in the elderly concluded that “World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only a few patients.”²⁶ Additional information on the efficacy of opioids for non-cancer pain and cancer pain is presented in Sections 4.2 and 4.3.

Oxycodone

Indications

Oxycodone is a strong opioid that acts at μ- and κ-opioid receptors. It has pharmacological actions similar to other opioids, but with a specific pharmacologic profile and greater analgesic potency than morphine.

Dosage

Oxycodone comes in an immediate-release form (5 mg IR capsules, or in combination products with aspirin [Percodan^®] or acetaminophen [Percocet^®]) for the relief of pain. It also comes in an extended-release or controlled-release form (Oxycontin^®). The controlled-release tablets come in doses of 10, 15, 20, 30, 40, 60, 80, and 160 mg CR formulation. The typical prescription is one tablet every 12 hours. The three latter doses (60, 80, and 160 mg) are for use only in opioid-tolerate patients. Oxycontin^® is effective for moderate-to-severe cancer pain and allows the convenience of every-12-hours administration. In most markets, oxycodone is significantly more expensive than morphine and is thus less attractive as a first-line analgesic for this and other reasons.

Adverse Effects

See “Opioid side effects” (Sec. 4.1.C) for information on the adverse effects of oxycodone.

Efficacy for Acute Pain

Oxycodone is a strong opioid agonist used to treat moderate to severe pain and, like morphine, it is not a first-line agent for management of postoperative pain in outpatients or for nonextensive acute trauma. One advantage of oxycodone and morphine is that they are not mandatorily formulated as a combined drug as are hydrocodone and codeine. This is an advantage for a patient who cannot take NSAIDs or acetaminophen for various reasons. A 2009 meta-analysis of the analgesic efficacy of oxycodone alone and in combination with acetaminophen in adults with moderate-to-severe acute postoperative pain concluded that oxycodone 15 mg alone compared with placebo yielded a number-needed-to-treat (NNT) score of 4.6 (defined as 50% pain relief); for oxycodone 10 mg plus acetaminophen 650 mg, the NNT was 2.7.²⁷

Efficacy for Chronic Pain

A number of randomized double-blind studies, comparing oxycodone versus morphine or comparing different release forms of oxycodone have demonstrated that the drug is equally as effective as morphine and in general is well tolerated in the treatment of cancer pain.^28–31

Fentanyl

Indications

Fentanyl is used for cancer-pain management and as a palliative medicine in the form of a transdermal patch (e.g., Duragesic^®), which is especially useful in those patients who do not have enteral (e.g., by mouth) access or for whom nausea and vomiting limit the ingestion of the required dose of opioid. However, fentanyl in a transdermal patch contains a high concentration of this potent Schedule II opioid agonist, resulting in a high potential for abuse and associated risk of fatal overdose due to respiratory depression.

Dosage

As this chapter does not cover the use of intravenous or injected opioids, the dosing for fentanyl citrate injections (50 µg/mL) is not discussed. Fentanyl in the transdermal patch has substantial limitations and risks and it is strongly recommended that it should only be used in patients who are already receiving opioid therapy and have demonstrated opioid tolerance and who require a total daily dose equivalent to or greater than 25 µg/h. Patients who are considered opioid-tolerant are those who have been taking at least 60 mg of morphine daily for a week or longer (or an equipotent dose of other Schedule II opioids).

Adverse Effects

The results of eight studies in cancer and noncancer pain were pooled and demonstrated that pain scores were significantly reduced with fentanyl but adverse events were high in active and placebo groups.³² See “Opioid side effects” (Sec. 4.1.C) for more details on opioid adverse effects.

Efficacy for Acute Pain

Fentanyl is not indicated for pain in the postoperative period.

Efficacy for Chronic Pain

The efficacy and tolerability of transdermal fentanyl for long-term treatment of cancer pain have been extensively studied and very well documented.^33–36

Hydromorphone

Indications

Hydromorphone is a water-soluble opioid that is several times more potent than morphine, allowing for smaller doses to be used. It is available in parenteral, rectal, subcutaneous, and oral formulations. It can also be administered via epidural and intrathecal routes. Hydromorphone should be considered particularly for patients on morphine who are having side effects of increased confusion or myoclonus.³⁷

Dosage

Hydromorphone comes in an immediate-release form and a continuous- or extended-release form. In non-opioid-tolerant patients, when used for acute pain, this medication is typically initiated at an oral dose of 2–4 mg every 4 hours. In elderly patients, the starting dose is usually lower. For chronic pain patients the dose and formulation of the analgesia (immediate or extended release) will vary substantially depending on the patient’s opioid tolerance. In chronic pain, doses should be administered around-the-clock and if needed a “rescue” or supplemental dose of 5–15% of the total daily dose may be administered every 2 hours. Periodic reassessment after the initial dosing is always required.

Adverse Effects

See “Opioid side effects” (Sec. 4.1.C) for information on the adverse effects of hydromorphone.

Efficacy for Acute Pain

Like morphine and oxycodone, hydromorphone is not indicated as a first-line medication for acute pain in the postoperative period following minor procedures, although it clearly has efficacy for acute pain.³⁸

Efficacy for Chronic Pain

A number of randomized double-blind studies, comparing hydromorphone vs. morphine or comparing different release forms of hydromorphone, have demonstrated that the drug is equal to or better than morphine and in general is well tolerated in the treatment of cancer pain.^39–41 One report uniquely suggested this medication is better at relieving continuous dull pain versus sharp intermittent cancer pains.⁴²

Oxymorphone

Indications

An oral immediate-release tablet formulation of oxymorphone is approved for the treatment of acute moderate-to-severe pain. This medication is also available as an extended-release formulation. Single doses of oxymorphone IR have been reported to provide significant pain relief after orthopedic surgery and dental surgery.

Dosage

Oxymorphone IR should be administered every 6 hours as 5- or 10-mg tablets. The extended-release form of oxymorphone hydrochloride (Opana-ER^®) comes in tablet strengths of 5, 10, 20, and 40 mg for oral administration every 12 hours.

Adverse Effects

See “Opioid side effects” (Sec. 4.1.C) for information on the adverse effects of oxymorphone.

Efficacy for Acute Pain

The extended-release, oral form of this medication (Opana-ER) is not indicated for pain in the immediate postoperative period due to the risk of oversedation and respiratory depression that outweighs the analgesic efficacy of the medication. A double-blind, placebo-controlled study evaluated three different doses of oxymorphone IR for efficacy and safety (compared with oxycodone IR) in patients with acute moderate-to-severe postsurgical pain.⁴³ Results showed that all oxymorphone IR doses were superior to placebo in pain-relief efficacy. Opioid-related adverse events for oxymorphone were equivalent to those seen with oxycodone and generally were of a mild or moderate level. This medica­tion, however, would not be a first-line choice for minor procedures.

Efficacy for Chronic Pain

Two independent randomized and controlled studies examined the efficacy of oral oxymorphone (extended-release form) for the treatment of chronic low back pain.^44,45 One study concluded that oxymorphone ER is generally well tolerated without unexpected adverse e/>