After Propoxyphene: Alternate Pain Medications

Scott Lothian, RPh


May 09, 2011


Now that propoxyphene is unavailable, what are other options for analgesia?

Response from Scott Lothian, RPh
Clinical Pharmacist, Oncology & Pain Management; Epic Beacon Analyst, Pharmacy Department, Northwestern Memorial Hospital, Chicago, Illinois

Recently, Xanodyne Pharmaceuticals, Inc. agreed to withdraw propoxyphene from the market at the request of the US Food and Drug Administration (FDA). New research found that propoxyphene, which was sold under the brand names Darvon®and Darvocet®, was associated with cardiac toxicity (prolonged QT interval, prolonged PR interval, and widened QRS complex) even at therapeutic dosing.[1] This article serves as a general overview of analgesics for clinicians now faced with finding alternative pain medications for their patients. Strong opioids (eg, morphine, hydromorphone, oxycodone, methadone) are not be discussed.


Acetaminophen (APAP) alone is as effective as the combination of propoxyphene and APAP for arthritis, postsurgical, or musculoskeletal pain.[2] Acetaminophen is well tolerated at recommended doses with relatively few side effects. However, long-term maximum daily dosing can lead to toxicities (hepatic and renal), especially if taken with excessive alcohol.[3] APAP now carries a black box warning in regard to the possibility of increased risk for severe liver injury.[4]

Patients should be advised not to exceed the maximum daily dose of APAP and to avoid taking other sources of APAP concomitantly.[3] The American Geriatrics Society (AGS) recommends that the maximum dose of APAP be reduced 50%-75% in patients with hepatic insufficiency or a history of alcohol abuse.[3]

In addition, the maximum daily dose of APAP may interfere with warfarin, causing an increased risk for anticoagulation and an increased international normalized ratio (INR). Patients on warfarin therapy should contact their healthcare professional if they start taking doses exceeding 2 g/day; close INR monitoring is required when starting or stopping high-dose APAP therapy.[5]

The FDA recently posted a safety announcement recommending that the content of APAP in all prescription combination products be limited to a maximum of 325 mg. This does not pertain to over-the-counter products.[4]


Available nonsteroidal anti-inflammatory drugs (NSAIDs) include nonselective agents, such as ibuprofen and naproxen, and selective agents, such as the cyclooxygenase (COX)-2 inhibitor celecoxib. NSAIDs have proven to be more effective than propoxyphene plus APAP for inflammatory or musculoskeletal pain.[6]

Many clinicians consider NSAIDs as the initial agent in most patients if there are no contraindications, whereas others believe that use should be limited to short-term treatment and will not recommend them for patients over 65 years of age.[3]

If NSAIDs are used and one agent is not effective, it is often worth trying another agent before giving up on NSAID-based pain therapy. According to an evidence-based review, ibuprofen should be considered first because it has the lowest risk for gastrointestinal adverse effects. Naproxen can be considered if other nonselective NSAIDs are required because it has an intermediate risk for adverse events. If single-agent analgesia is inadequate, NSAIDs may be combined with APAP or opioids.[7]

The FDA has provided guidance on the use of NSAIDs[7]:

  • The lowest effective dose of NSAIDs should be used for the shortest duration.

  • NSAIDs should be avoided in high-risk patients (eg, history of ischemic heart disease, stroke, congestive heart failure, or those having recently undergone a coronary artery bypass graft).

  • Nonselective NSAID use in patients < 65 years of age without gastrointestinal risk factors is generally appropriate.

  • Nonselective NSAID use alone is inappropriate in patients with a history of a previous gastrointestinal event and in those receiving aspirin, steroids, or warfarin. These patients should receive concomitant proton-pump inhibitor (PPI) therapy or therapy with a COX-2 inhibitor.

  • Therapy with a COX-2 inhibitor and a PPI is appropriate only in patients at very high risk for a gastrointestinal event.

In addition, the AGS recommends that older persons taking nonselective NSAIDs should receive mucoprotective agents, and patients taking any NSAIDs should be routinely assessed for gastrointestinal and renal toxicity, hypertension, heart failure, drug-drug interactions, and drug-disease interactions.[3]

All NSAIDs carry a black box warning in regard to the possibilities of increased risk for serious cardiovascular thrombotic events, stroke, and myocardial infarction as well as serious gastrointestinal events such as bleeding, ulceration, and perforation.[8]

Opioid-like Agents

Tramadol is a centrally acting analgesic indicated for moderate to moderately severe pain.[9] One study found that tramadol demonstrated comparative efficacy to propoxyphene with APAP.[6]

Tapentadol (Schedule II), another centrally acting analgesic, is indicated for moderate-to-severe acute pain. Both tramadol and tapentadol are thought to work by mu-opioid agonist activity and inhibition of norepinephrine reuptake; tramadol also inhibits serotonin reuptake. (Tapentadol may increase serotonin levels, but this is not considered a mechanism of its analgesic effect.[9,10]) These agents are especially suited for pain with a neuropathic component; they may not be as effective for moderate pain that is usually well treated by traditional opioid combinations or other agents if a neuropathic component is absent.

Drug interactions may limit use of these agents. Because both can potentially increase serotonin levels, they should not be given concurrently with serotonergic drugs such as monoamine oxidase inhibitors (MAOIs), triptans, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors due to the increased risk for seizures and serotonin syndrome.[9,10] Tapentadol is contraindicated with concomitant use or use within 14 days of MAOIs.[10] Side effects of both include dizziness, nausea, vomiting, and constipation.[9,10] Because tapentadol is a newer analgesic, its role has yet to be proven in wider clinical use.

Opioid Combination Products

Combination opioids such as APAP with codeine or APAP with hydrocodone are effective for the short-term treatment of most types of moderate pain. Long-acting agents should be considered for baseline pain control of well-established chronic pain to avoid chronic short-acting opioid use.[3] Constipation, even with limited use, is almost always an issue and should be treated prophylactically with a stimulant/softener laxative. Due to concerns of addiction, opioids are often underused. Full assessment of the patient's pain and history may help to better define their proper use in most patients, but in the end, good pain control should be the defining factor.

Other Agents

Topical agents (eg, lidocaine, capsaicin) and pain adjuvants such as antidepressants (eg, nortriptyline, desipramine, duloxetine), muscle relaxants (eg, tizanidine, baclofen), anticonvulsants (eg, gabapentin, pregabalin), and others may be considered for combination therapy or as the lone agent if indicated by the type of pain.[3]


When selecting an analgesic, one should evaluate the pain fully to determine the most appropriate agent(s); prescribe an agent that will not be needed at its maximum dosage for a prolonged period of time; and consider the patient's age, history, and comorbidities. Guidelines[3,11] and algorithms[7] are available that can assist clinicians in choosing appropriate analgesic and mucoprotective therapy.


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