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14 Articles in Volume 21, Issue #5
Analgesics of the Future: Interleukin-17 Inhibitors for Treating Psoriatic Arthritis
Ask the PharmD: What evidence exists for metformin in treating rheumatoid arthritis pain?
Case Chat: Spasms vs. Spasticity and Muscle Relaxant Options
CDC Opioid Prescribing Guideline Updates Are in the Works: Will the Changes be Enough?
Chronic Pain Management in Marginalized Populations: How to Rebalance the Provider-Patient Relationship
Dantrolene: The Forgotten Molecule for Outpatient Spasticity
Forgotten Analgesics: The Drugs Pain Practitioners Need to Reconsider
Machine Learning Predicts Patient Response to Rheumatoid Arthritis Therapy
Perspective: Where Have All the Rheumatologists Gone?
Rheumatoid Arthritis and Bridge Therapy: Primary Care Considerations
Root Cause of Plantar Fasciitis: Three-Step Exercise Protocol
Shoulder Pain and Rotator Cuff Injuries: Emerging Treatments
Special Report: The Evolution of Rheumatoid Arthritis Treatment, from Gold to Gene Therapy
Transfer of Care: Barriers and Solutions in Chronic Pain Management

Forgotten Analgesics: The Drugs Pain Practitioners Need to Reconsider

A review of pain medications of the past and how they may help to optimize the treatments of today.

Pain-treating clinicians are constantly searching for medications that improve patient outcomes and/or that can minimize the use of opioids. Perhaps, older treatment modalities just need to be reconsidered.



The management of pain – whether acute or chronic – is one of the most difficult medical conditions to treat and when treatment options are limited, the patient is the one left to suffer while the clinician bears the burden of trying to help the patient. The current opioid crisis in the US has significantly shifted the pendulum of opioid prescribing practices due to various restrictive guidelines, laws, regulations, and policies at both the federal and state level. Clinicians are challenged and quite possibly hesitant with managing complex pain syndromes in individuals with medical comorbidities.

Not all pharmacologic treatment options are viable for every case due to patient-specific factors, compelling medical indications and comorbidities, drug interactions, and even pharmacogenetics. Over time, some pharmacologic options are withdrawn from the market by the manufacturer, forgotten, or underutilized due to a lack of clinician knowledge or familiarity.

Here, we revisit this “land of lost analgesics” with the goal of refamiliarizing pain-treating clinicians – whether in specialty or primary care – with alternative treatment options that are worth consideration when initial first and second-line pain therapies have been optimized or are contraindicated. Potential uses, clinical considerations, and US availability are noted for each.

Not all pharmacologic treatment options are viable for every patient. Here, we revisit the “land of lost analgesics” with the goal of refamiliarizing pain-treating clinicians – whether in specialty or primary care – with alternative treatment options. (Image: iStock)


Skeletal Muscle Relaxants

Skeletal muscle relaxants are a broad category of medications consisting of a wide spectrum of drugs with different indications and mechanisms of action. Muscle relaxants can be divided into two main categories: antispasmodic and antispasticity medications. Antispasmodics are used to reduce muscle spasms resulting from a painful condition whereas antispasticity medications are used to decrease spasticity that hinders functionality.1                   

Orphenadrine citrate

Orphenadrine citrate is classified as an antispasmodic with the mechanism of action being unclear, but is a derivative of diphenhydramine and its activity is believed to be related to its sedative effects. In four placebo-controlled trials, orphenadrine was found to be fairly effective in some musculoskeletal conditions (acute low back pain, neck pain, nocturnal leg cramps) as well as symptoms of pain intensity, stiffness, and functionality.2

However, given orphenadrine’s chemical nature, it consequently possesses anticholinergic activity and thus patients may experience dry mouth, blurry vision, constipation, urinary retention, and cognitive dysfunction.1 Orphenadrine citrate is indicated for mild to moderate pain of acute MSK disorders and as an adjunct to rest, PT, and other measures for relief of discomfort associated with acute painful MSK conditions. In 2020, FDA granted a supplemental ANDA for a combination formulation of orphenadrine citrate with aspirin and caffeine in 2020.

  • Brand names: Norflex, Norgesic, Orphenesic Forte
  • Formulations: oral, injectable
  • Potential targets: acute low back pain, neck pain, nocturnal leg cramps
  • Available in US: Yes


Tolperisone is classified as an antispasmodic with the mechanism of action possessing lidocaine-like-activity by stabilizing nerve membranes of mono- and polysynaptic reflexes in the spinal cord by blocking in a dose-dependent manner.1 Tolperisone was shown to be more effective than placebo for patients with chronic low back pain and overall improvement with short term use over 21 days, but no reduction of muscle spasms or pain.1 Unlike other skeletal muscle relaxants, tolperisone has been shown to exhibit less somnolence or cognitive adverse effects when used with for up to 14 days.3 As a skeletal muscle relaxant with less CNS adverse effects than currently available in some analgesics, tolperisone may offer a more promising option for patients.

  • Brand names: Mydocalm
  • Formulation: oral
  • Potential targets: low back pain
  • Available in US: No, but the manufacturer is recruiting for Phase 3 STAR study under ClinicalTrials.gov #NCT04671082; utilized in Europe since the 1960s

Dantrolene sodium

Dantrolene is classified as an antispasmodic medication with the mechanism of action on the PNS by blocking the calcium channel of the sarcoplasmic reticulum to reduce the concentration of calcium and diminishing the potential for an actin-myosin interaction which could produce a muscle contraction.1,2 Dantrolene has shown some efficacy for use in spasticity in debilitating conditions that hinders functionality, but there is little evidence exhibiting effectiveness for musculoskeletal conditions.1 Despite dantrolene bypassing the CNS and avoiding the typical adverse effects, it is consequently associated with hepatotoxicity and muscular weakness.1

Dantrolene is still commercially available in oral and injectable formulations and FDA approved for the treatment of spasticity associated with upper motor neuron disorders such as cerebral palsy, multiple sclerosis, spinal cord injury, and stroke.

  • Brand names: Dantrium, Ryanodex
  • Formulations: Oral, injectable
  • Potential targets: Muscle relaxation after CNS injury
  • Available in US:  Yes

See also, a case report and review of dantrolene for muscle spasticity. 

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs are used to inhibit the enzyme cyclooxygenase (COX) which is a bifunctional membrane-bound hemoproteinthat catalyzes the reduction of arachidonicacid to cyclic endoperoxide by bis-dioxygenation for the biosynthesisof prostaglandins, prostacyclin and thromboxanes.4

There are two principle isoforms of COX enzymes which are bifunctional enzymes consisting of both cyclooxygenase and peroxidase activity: COX-1 and COX-2. COX-1 is predominantly responsible for the production of prostaglandins necessary for maintaining normal endocrine and renal function, gastric mucosal lining, and hemostasis by mediating thromboxane A2 production to cause vasoconstriction and activate platelet aggregation. COX-2 is produced in response to inflammatory and mitogenic stimuli which is important in facilitating inflammation as well as the production of prostacyclin to promote vasodilation and inhibit platelet aggregation.5


Rofecoxib is a COX-2 selective NSAID consisting of a methylsulfone moiety and a lactone ring structure that makes it >800 times more selective for COX-2 than COX-1.6 In comparison to other NSAIDs, rofecoxib is about 6 to >20 times more selective for COX-2 than celecoxib, diclofenac, indomethacin, or meloxicam. As an NSAID with significant COX-2 specificity, rofecoxib has benefits of yielding effective analgesic and anti-inflammatory activity with reduced potential for GI-related adverse effects.6 Rofecoxib was originally FDA-approved for the management of acute pain in adults, primary dysmenorrhea, and osteoarthritis.4,6        

In a Cochrane review of 26 RCTs evaluating the efficacy and safety of rofecoxib use in osteoarthritis compared to placebo, celecoxib, diclofenac, ibuprofen, naproxen, nimesulide, nabumetone, acetaminophen, and diclofenac/misoprostol combination, evidence showed that rofecoxib was more effective than placebo, but displayed no difference in efficacy when compared to the other NSAIDs at equivalent doses. From a safety standpoint, rofecoxib resulted in fewer GI-related adverse effects compared to celecoxib, ibuprofen, and naproxen with only one trial comparing rofecoxib to celecoxib reporting on the overall rates of GI-related adverse events comparing high dose rofecoxib with low dose celecoxib.7

In a similar fashion, three trials examining cardiovascular safety of rofecoxib and celecoxib used non-comparable doses with the results of those studies suggesting that rofecoxib caused more patients to experience a significant increase in systolic blood pressure and peripheral edema. However, there was no difference between rofecoxib and celecoxib in studies conducted among the general populations.7

In another Cochrane review of two RCTs evaluating the efficacy and safety of rofecoxib use in rheumatoid arthritis, one trial compared to placebo which rofecoxib exhibited a greater degree of efficacy while having a similar a safety profile.The second trial, known as the VIOXX GI Outcomes Research (VIGOR) study,was primarily designed to assess the safety of rofecoxib compared to naproxen which showed similar efficacy and lower GI-related adverse effects and bleeding, but consequently revealed a greater incidental finding of non-fatal myocardial infarctionsin the rofecoxib population.8,9

Fortunately, the overall mortality rate and rate of death from cardiovascular causes were similar in the two study groups. In another significant study, the Adenomatous Polyp Prevention on VIOXX (APPROVe) trial compared rofecoxib to placebo to evaluate its effectiveness in preventing the recurrence of colon polyps, but was unfortunately terminated prematurely due to increased incidence of myocardial infarctions and ischemic cerebrovascular eventsinitially seen following 18 months of continuous treatment.9,10

Similar to other NSAIDs with nephrotoxic adverse effects, rofecoxib causes dose-independent reductions in glomerular filtration rate and acute renal failure as well as reversible interstitial nephritis.11 Rofecoxib was subsequently voluntarily withdrawn from the market in September 2004. However, other COX-2 selective NSAIDs such as celecoxib, diclofenac, etodolac, and meloxicam are still commercially available for clinical use.


Benoxaprofen is a arylalkanoic and proprionic acid derivative NSAID initially FDA-approved for the treatment of osteoarthritis and rheumatoid arthritis. Unlike other NSAIDs, benoxaprofen is a weak COX inhibitor, but also has an additional mechanism of action by inhibiting 5-lipoxygenase and mononuclear leukocyte migration and their chemotactic response. Benoxaprofen had a long elimination half-life 28-35 hours which allowed for once daily dosing making it convenient for clinicians to prescribe and patients to be adherent to therapy.12,13

There was strong consideration that benoxaprofen had disease-modifying effects in rheumatoid arthritis.13 A clinical trial in 2,204 patients with either active rheumatoid arthritis or symptomatic osteoarthritis treated with benoxaprofen for an average period of 14 months was shown effective for continuous antirheumatic stabilization with a single daily dose.14

Compared to other NSAIDs in rheumatoid arthritis and osteoarthritis, benoxaprofen has been shown to be more effective than aspirin or ibuprofen and more effective than ibuprofen with comparable efficacy to aspirin respectively.14 When benoxaprofen was compared to other NSAIDs such as indomethacin, naproxen, and sulindac, there was no significant difference in efficacy with rheumatoid arthritis patients.12

From an adverse effect profile, benoxaprofen is somewhat unique as it is associated with low incidences of peripheral edema and peptic ulcers, but has a high frequency of phototoxicity and onycholysis.12,14 Photosensitivity typically appears within 48 hours of treatment initiation and resolves 48 hours following discontinuation. Unfortunately, benoxaprofen was voluntarily withdrawn from manufacturer due to cholestatic jaundice with nephrotoxicity and hepatotoxicity. However, benoxaprofen is not unique with respect to its dual activity as a weak inhibitor of COX and its inhibitory effects on mononuclear leukocytes as sulindac has comparable potency and is still commercially available for clinical use.12

Choline Magnesium Trisalicylate

Choline magnesium trisalicylate (CMT) is a non-acetylated salicylate arylpropionic acid and arylacetic acid derivative NSAID that structurally contains choline salicylate and magnesium salicylate with analgesic and anti-inflammatory properties similar to aspirin. CMT does not inhibit platelet aggregation induced by two physiological aggregating agents, collagen and arachidonic acid or spontaneous platelet aggregation.15 The acetyl moiety on aspirin’s hydroxyl group facilitates it to alter factors of platelet function by irreversible acetylation of COX and thus inhibits the conversion of arachidonic acid to thromboxane A2 resulting in suppressing platelet aggregation and prolonged bleeding time. Unlike aspirin, CMT lacks an acetyl moiety and has choline and magnesium substituents on the carboxyl groups of the three salicylate molecules in its structure and as a result there is no interference with platelet aggregation or effect on bleeding.16

CMT may be an alternative NSAID for patients prescribed lithium as non-acetylated salicylates may be preferred to minimize risk for potential drug interactions and inducing lithium toxicity.17 However, CMT should still be used with caution and or avoided in patients with renal dysfunction, and compelling cardiovascular comorbidities such as congestive heart failure and coronary artery disease while prescribed other anticoagulants such as P2Y12 antagonists, phosphodiesterase-3 enzyme inhibitors, vitamin k antagonists, and direct-acting oral anticoagulants.

The most common adverse effects with CMT are similar to traditional NSAIDs with tinnitus and gastrointestinal issues (ie, gastric upset, heartburn, epigastric pain, diarrhea). CMT is FDA-approved for use in the relief of mild to moderate pain, management of acute painful shoulder, management of pyrexia, relief of sighs/symptoms of osteoarthritis, rheumatoid arthritis, and other arthritis (long-term management and acute flares), and anti-inflammatory or analgesic management (in children) of juvenile idiopathic arthritis and other appropriate conditions.


Zomepirac is a pyrrole acetic acid a NSAID structurally similar to tolmetin, but is more lipophilic and may potentially have central analgesic effects. Zomepirac is nearly equivalent in potency to indomethacin and tolmetin as a COX-1 inhibitor of prostaglandin synthesis and was 2 or 3 times less active than diclofenac, but more active than aspirin, ibuprofen, or naproxen.Zomepirac is typically dosed 100 mg every 4 to 6 hours as needed, but should not be dosed greater than 400mg/day for three months or longer or exceed 600mg/day as these doses have not been studied and are not recommended.18,19

In looking at the data, zomepirac has demonstrated efficacy in relieving moderate to severe acute postoperative orthopedic, gynecologic, abdominal, and thoracic as well as dental pain.18-20 Zomepirac displayed greater efficacy over some opioids and may have been considered a viable option as an opioid sparing analgesic. In singe-dose studies in patients with acute pain, zomepirac 100mg exhibited greater efficacy compared to codeine 60 mg as well as other single agent non-opioid analgesics and other analgesic combinations. In single-dose crossover studies comprised of patients with moderate to severe postoperative pain, oral zomepirac 100 or 200mg was compared to intramuscular morphine 16mg and provided comparable analgesic effects and suggesting a “ceiling effect” of analgesic activity while also indicating that oral zomepirac was about one-sixth as potent as intramuscular morphine, but with a slower onset and longer duration of action.19

Adverse effects of zomepirac are fairly similar to other commonly prescribed NSAIDs such as gastrointestinal-related, however zomepirac exhibited a higher incidence of urogenital symptoms (ie. dysuria, cystitis, urinary frequency, hematuria, pyuria, and urinary tract infections) compared to other common NSAIDs and should be monitored more closely if used longer than six months. Following a single 200-mg dose, zomepirac sodium was shown to prolong the template bleeding time and decrease platelet retention significantly. Unlike aspirin and similar to other NSAIDs, zomepirac platelet inhibition is reversible and returns to normal function after 24 to 48 hours following discontinuation of therapy.18,20 Unfortunately, zomepirac was voluntarily withdrawn in due to various case reports of anaphylactic reactions. However, other COX-1 selective NSAIDs such as indomethacin and tolmetin with similar potency are still commercially available for use clinically applicable.

  • Brand names: Zomax
  • Formulation: oral
  • Potential targets: moderate to severe acute postoperative orthopedic, gynecologic, abdominal, thoracic, and dental pain
  • Available in US: No


Adjuvant Analgesics

Neuropathic pain can be one of the more challenging pain syndromes as intolerable symptoms may be intermittent, constant, aggravated, or spontaneous. Adjuvant analgesics consisting of antidepressants, anticonvulsants, as well as other medications with unique properties affecting the nerve cell membrane may be used to help minimize the frequency and intensity in alleviating neuropathic pain symptoms. Some adjuvant analgesics may benefit other medical conditions as well, such as comorbid mental health disorders, potentially minimizing the need for polypharmacy and pill burden.


Maprotiline is a dibenzo-bicyclo-octadiene secondary amine tetracyclic antidepressant with a large lipophilic carbocyclic moiety and is distinguishable from tricyclic antidepressants by the presence of an ethylene bridge rendering its three-dimensional stereochemical configuration. Maprotiline exhibits similar activity as amitriptyline and imipramine, but has a more rapid onset of action and less anticholinergic adverse effects.21,22

Similar to imipramine, maprotiline exhibits strong norepinephrine reuptake inhibition activity across the nerve cell membrane as well as weak alpha-2 adrenergic blocking activity. Maprotiline undergoes first-pass hepatic metabolism primarily by N-demethylation, oxidative deamination, and aliphatic and aromatic hydroxylation to active formation of aromatic methoxy derivatives.21, 22 Maprotiline may initiated at 75 mg/day and can be titrated up to 225-300mg/day.22

In a double-blind cross over study with maprotiline 75mg/day compared to placebo in patients with chronic tension headache, treatment with maprotiline over a 6-week period was shown to be superior to placebo with mild side effects (drowsiness, dry mouth, increased appetite/weight gain).23 A study group consisting of patients with pain and depression were treated with maprotiline and gradually titrated to a target dose up to 300mg/day (150mg/day if 60 years or older) as tolerated resulted in 72% of patients responding with a greater than a 50% reduction in pain.24 In a randomized, double-blind, crossover trial, maprotiline was compared with amitriptyline in the treatment of postherpetic neuralgia displaying some pain relief, but was not as effective as amitriptyline unless treatment with amitriptyline had failed.25

Maprotiline has similar adverse effect profile as traditional tricyclic antidepressants given its anticholinergic activity with dizziness/faintness, blurry vision, dry mouth, constipation, orthostatic hypotension and tachycardia, but to a lesser degree as well as cutaneous rashes which are more common. Cardiovascular effects have been demonstrated with maprotiline as it can cause a decrease in standing systolic pressure, flattening of T-waves, an increase in heart rate and PR interval, prolongation of the pre-ejection period, as well as QT prolongation.22

  • Brand names: Ludiomil
  • Formulation: oral
  • Potential targets: depressionand anxiety
  • Available in US: Yes

More on the overlap between chronic pain conditions and psychiatric disorders.




Mexiletine is a class 1B antiarrythmic agent FDA-approved for the treatment of ventricular arrhythmias. Pharmacologically, mexiletine is a structural analogue of lidocaine and acts by blocking voltage-gated sodium channels decreasing the rate of depolarization of ventricular cardiac myocytes, but also has similar potency in local anesthetic properties.26,27

Mexiletine is a racemic mixture of R-(–)- and S-(+)-enantiomers that possess characteristic antiarrhythmic potency with the R-(–)-enantiomer exhibiting increased cardiac sodium channel binding and greater antiarrhythmic activity than the S-(+)-enantiomer, but neither of the isomers significantly changed the electrocardiographic intervals (PR, QRS, QTc) or refractory periods.26 Mexiletine has been used to treat various neuropathic pain syndromes including: alcoholic neuropathy, cancer and radiation-induced neuropathic pain, painful diabetic neuropathy, dysaesthetic pain associated with multiple sclerosis, HIV-induced neuropathy, myofascial pain, peripheral nerve disease, phantom limb pain, postherpetic neuralgia, spinal cord injury, thalamic (post-stroke) pain, and trigeminal neuralgia.28

Mexiletine has a narrow therapeutic range from 0.75 to 2 mg/L that correlates serum concentration level to both its antiarrhythmic efficacy as well as adverse effects.26 However, there are no serum mexiletine concentration levels that correlate with efficacy in relieving neuropathic pain syndromes that have been studied. Therapeutic doses of mexiletine have ranged from 300 to 675mg/day, but clinicians should be vigilant and avoid dosages that can result in serum concentrations exceeding >2 mg/L. Mexiletine is predominantly hepatically metabolized via CYP2D6 to p-Hydroxymexilitine so dosage adjustments are not necessary in patients with severe renal dysfunction or on hemodialysis.28 The consequences of genetic polymorphism to CYPD6 in patients receiving mexiletine for neuropathic pain remain unclear, but should be used with caution and monitored closely during initiation and dose titrations especially in the setting of potential clinically significant drug-drug interactions.26,28

Opioids may have a potential clinically significant drug interaction with mexiletine. Despite there being no studies designed to evaluate the effects of opioids on the pharmacokinetics of mexiletine, it has been reported that patients taking morphine have significantly lower mean concentrations of mexiletine 3 hours following the first dose. The mechanism caused by the lower mexiletine serum concentration is believed to be due to opioids inhibiting gastric emptying and in turn slowing the absorption of mexiletine.26 (More on opioids below.)

The most common adverse effects patients may experience with mexiletine are dizziness or lightheadedness, tremor, nervousness, ataxia, nausea, anorexia, and gastric irritation, but tolerability may be improved with food or reducing the dose.27 Mexiletineis still commercially available in oral formulations and FDA-approved for the management of ventricular arrhythmias, but may potentially be an alternative option as an adjunct analgesic for neuropathic pain who have failed response or cannot tolerate first line treatment options.

  • Brand names: Mexitil
  • Formulation: oral
  • Potential targets: neuropathic pain
  • Available in US: Yes



Opioids are not just purely mu-opioid agonists; some can be mixedmu opioid receptor agonist-antagonists, as well as agonists of the delta and or kappa opioid receptors with varying pharmacodynamic effects. Mixedmu opioid receptor agonist-antagonists are not used as often as full mu-opioid agonists due to their limited commercial availability, but as a result of their antagonist activity has less dependence and abuse potential.

Opioid analgesics may be considered as adjunctive therapy upon initiation and during optimization of non-opioid analgesics especially for severe pain, but dose and duration of therapy should be kept to a minimum where possible and consideration should be made to taper toward discontinuation as goals of therapy are met and as overall pain improves with optimization of non-opioid analgesics. If opioids are to be used, risk mitigation strategies such as obtaining an opioid treatment agreement or consent, review of prescription drug monitoring program reports, and conducting urine drug testing should be performed periodically as clinically indicated as recommended per established clinical practice guidelines as well as state regulations.


Butorphanol is a synthetic phenanthrene kappa opioid receptor agonist, mixed mu opioid receptor agonist-antagonist, as well as apartial sigma receptor agonist which is responsible for psychotomimetic effects such as dysphoria, respiratory and vasomotor stimulation.29 potency of parental butorphanol ranges from 4 to 8 times more than morphine, 30 to 40 times more than meperidine, and 15 to 24 times more than pentazocine whereas oral is about 7 times more than codeine and 6 times more than pentazocine.29,30

Butorphanol’s antagonist activity is about 30 times more than pentazocine while only a fraction (1/40) of naloxone and given its high binding affinity to the mu opioid receptor, higher doses of naloxone may be necessary in order to reverse any adverse effects of butorphanol compared to pure opioid agonists such as morphine.29 The absorption of butorphanol is adequate via oral and parenteral routes, but undergoes extensive first-pass hepatic metabolism primarily by hydroxylation to the major metabolite hydroxybutorphanol and N-dealkykation to minor metabolite norbutorphanol which leaves oral bioavailability yielding about only 5 to 17%. With transnasal administration of butorphanol on the other hand, this route of administration bypasses the gastrointestinal tract, and improving bioavailability to about 48 to 70% similar to parenteral administration.30

Additionally, transnasal butorphanol absorbs rapidly while providing onset of analgesia within 15 minutes making it an ideal short-term treatment option for patients with moderate to severe acute postoperative, musculoskeletal and migraine headache pain. The bioavailability and pharmacokinetics of transnasal butorphanol may be influenced by age and sex as the median value for tmax was marginally higher in the elderly (older than 65 years) in elderly men (75%), but was significantly lower in elderly women (48%). However, the bioavailability in young men (68%) and young women (70%) the Cmax and AUC values were relatively similar.30

The most common adverse effects to be expected from butorphanol are sedation, drowsiness, dizziness, as well as nausea and/or vomiting. Unlike pure opioid agonists such as morphine which can cause respiratory depression in a dose proportional manner, butorphanol exhibits a 'ceiling effect' with respect to the degree of respiratory depression such as increasing doses beyond 2mg may not result in a corresponding increase in degree of respiratory depression, but the duration of respiratory depression increases with higher doses.29,30 Butorphanol has hemodynamic effects similar to pentazocine but to a lesser degree with cardiovascular effects consisting of: increased pulmonary artery and wedge pressure, increased left ventricular end diastolic pressure, increased systemic arterial pressure, increased pulmonary vascular resistance, as well as increases to cardiac index and cardiac work.29

Considering these cardiovascular effects, butorphanol should be used with caution or avoided where possible in patients with acute myocardial infarction, coronary insufficiency, or ventricular dysfunction. Butorphanol is FDA-approved for use in the relief of moderate to severe pain, as a supplement to balanced anesthesia, for the relief of postpartum pain, and as preoperative or preanesthetic medication with the ladder three indications utilizing injectable formulations only.29

  • Brand names: Stadol (International)
  • Formulation: nasal, injectable
  • Potential targets: moderate to severe pain, postpartum pain, perioperative
  • Available in US: Yes (generic); Stadol (US) was discontinued due to severe hypertension


Nalbuphine is a semi-synthetic phenanthrene kappa opioid receptor agonist and mixed mu opioid receptor agonist-antagonist structurally similar to oxymorphone and naloxone.29,31,32The potency of parental nalbuphine is equivalent to approximately 0.7 to 0.8 times that of morphine whereas oral is 3 times more than codeine.29,32

In comparison to pentazocine, nalbuphine is about 3 to 4 times more potent with a longer duration of action and 10 times more effective with its antagonist activity.29,31 Similar to butorphanol, nalbuphine exhibits sufficient absorption via oral and parenteral routes, but undergoes extensive first-pass hepatic metabolism with oral bioavailability yielding only about 20%.29

Much like any other opioid, the most common adverse effects exhibited with nalbuphine include sedation, drowsiness, dizziness, as well as nausea and/or vomiting.29 Comparable to butorphanol, nalbuphine also exhibits a “ceiling effect”, but to both the degree and duration of respiratory depression as escalating doses does not prolong the duration of respiratory depression beyond 3 hours regardless of dose and thus resulting in a plateau of the respiratory depression curve.29,31,32 In a study comparing nalbuphine and morphine in patients with acute myocardial infarction, nalbuphine did not cause any adverse clinical or hemodynamic effects despite decreasing heart rate and contractility, but maintained aortic pressure and hence sustaining the balance between myocardial oxygen supply and demand.29

Nalbuphine’s cardiovascular benefits with decreasing heart rate and contractility while maintaining aortic perfusion pressure may prevent further cardiac ischemia in patients with acute myocardial infarction. Nalbuphine is FDA-approved for use as an analgesic for moderate to severe pain, for preoperative analgesia, as a supplement to surgical anesthesia, and as obstetrical analgesia during labor.29

  • Brand names: Nubain
  • Formulation: injectable
  • Potential targets: moderate to severe pain, perioperative, labor
  • Available in US: Yes


Propoxyphene is a synthetic diphenyl heptane mu opioid receptor agonist, kappa opioid receptor agonist, and noncompetitive N-methyl-D-aspartate (NMDA) receptor antagoniststructurally similar to methadone that has two centers of asymmetry and exists as four stereoisomers: alpha-dextrorotatory isomer, alpha-levorotatory isomer, dextropropoxyphene, and levopropoxyphene. Dextropropoxyphene exhibits analgesic activity and levopropoxyphene has antitussive activity while the other levorotatory isomers are relatively inactive, but overall none of the isomers can be converted into methadone.Propoxyphene is about 33.33% to 50% the potency of codeine which is deemed to be less efficacious than a 650 mg dose of aspirin.Propoxyphene has rapid absorption via oral route and undergoes extensive first-pass hepatic metabolism primarily by N-demethylation to norpropoxyphene and yielding bioavailability of about only 18-25% from a 65mg dose. Propoxyphene is both a CYP450 2D6 inhibitor and substrate and consequently may be subjected to genetic polymorphisms as well as potential drug interactions.33,34

In a review written by Miller and colleagues, among 243 articles referencing propoxyphene, only 20 double-blind or triple-blind clinical studies were identified creditable for review. Fifteen studies showed that codeine at lower or equal analgesic doses produced comparable or greater analgesic efficacy than propoxyphene, but within the same parameters no study demonstrated that codeine was inferior to propoxyphene. Seven studies showed that aspirin alone or aspirin in combination with phenacetin, and caffeine (at various doses) were comparable or had greater analgesic efficacy than propoxyphene.35

Not all of the comparison studies reviewed presented propoxyphene as inferior as two separate studies showed that propoxyphene hydrochloride 65 mg was superior to codeine 32.5 mg and aspirin 325 mg alone. When compared to placebo, nine studies showed propoxyphene to be superior while seven other studies it was not.35

Common adverse effects with propoxyphene are similar to other opioids which include: dizziness, lightheadedness, visual disturbances, somnolence, drowsiness, seizures, euphoria, nausea, vomiting, abdominal pain, constipation, urinary retention. The metabolite norpropoxyphene is primarily renally eliminated and if accumulated may result in potentially fatal CNS, cardiac, and respiratory adverse events such as cardiac arrest, pulmonary edema, seizures, and even mortality.34

Norpropoxyphene has more potent direct cardiac adverse effects which include: an increase in bradycardia, decreased contractility, decreased electrical conductivity, QTc interval prolongation, as well as local anesthetic properties similar to lidocaine or quinidine which may precipitate arrhythmias. Incidents of pulmonary edema and seizures were believed to be secondary to propoxyphene and its metabolite norpropoxyphene in both high-risk patients and at high doses. Prior to removal, propoxyphene was falling out of favor by clinicians and was perceived to have no therapeutic benefit in the management of acute and/or chronic pain while having greater mortality risk due to its cardiac and neurologic toxicity profile.34

In 2009, the FDA required the drug manufacturer to conduct a multiple-ascending dose (MAD) study which was a randomized, double-blind, placebo-controlled sequential multiple-ascending dose study of propoxyphene for 11 days evaluating 600 mg and 900 mg cohorts. The results of the MAD study were submitted to the FDA by the manufacturer showing significant QTc interval prolongations observed with propoxyphene 600 mg and 900 mg dose cohorts. In 2010, the FDA concluded that the safety risks of propoxyphene outweighed the benefits and recommended against its use due to significant abnormal heart rhythm and electrical activity changes with the prolonged PR interval, widened QRS complex and prolonged QT interval at therapeutically prescribed doses.36 

Propoxyphene was withdrawn by the manufacturer promptly afterward due to the FDA’s cardiotoxicity warning. Other short-acting immediate-release opioids such as codeine, hydrocodone, and oxycodone alone or in combination with acetaminophen are still currently available for use in acute severe breakthrough pain as clinically indicated.

  • Brand names: Darvocet-N (propoxyphene and acetaminophen)
  • Formulation: oral
  • Potential targets: breakthrough pain
  • Available in US: No, but similar products are still available


Levorphanol has been referred to as the “forgotten opioid” that is phenanthrene mu, delta, and kappa opioid receptor agonist and non-competitive NMDA receptor antagonist structurally similar to morphine, but without an oxygen and a 6-hydroxyl group.37-39 Similar to morphine, levorphanol has anticholinergic effects and like methadone, levorphanol inhibits the uptake of serotonin and norepinephrine.38 However, unlike methadone, levorphanol has a shorter and more predictable half-life of about 11 to 16 hours with a longer duration of action, and no CYP450 or P-gp drug interactions or associated with any QTc prolongation risk.37

Levorphanol exhibits good absorption through the intramuscular, subcutaneous, and oral routes of administration and undergoes phase II metabolism via glucuronidation to levorphanol-3-glucuronide that is renally eliminated. In some special populations such the elderly, palliative care, and SCI patients, levorphanol may be a viable option and may require a lesser need for coadministration of adjuvant analgesics.37

Common adverse effects with levorphanol are similar to other opioids such as nausea, vomiting, sedation, dizziness, constipation, pruritis, urinary retention, but a unique adverse effect is a potential increase in bile duct pressure which should be avoided in bili­ary surgery patients.39 Levorphanol is FDA-approved for management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

  • Brand names: Levo-Dromoran
  • Formulation: oral
  • Potential targets: severe pain
  • Available in US: Yes


Clinical Takeaways

Pharmacologic options of the past for treating acute, chronic, and perioperative pain may still be of clinical use. While some analgesic medications, including adjuvants, have been voluntarily withdrawn from the market by the manufacturer, others are still available and simply remain forgotten or underutilized. Pain practitioners across specialties are encouraged to refamiliarize themselves with these drugs in case they may benefit a particular patient who is refractory to or contraindicated for more widely used products.

Not all pharmacologic treatment options, however, are viable for every case; as with any prescription, risks and benefits must be weighed. Having a fuller, even if older, arsenal of potential treatment modalities for pain management can only serve to benefit the clinician and the patient. All pharmacologic treatment options old and new should be reconsidered based within patient-specific clinical parameters and trialed as potential alternative analgesics where possible.


Miguel Escanelle, MD, and Christopher P. Emerson, MD, MS, contributed to the research of this article.

This commentary is the sole opinion of the author and does not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies mentioned or specific drugs discussed.  It was not prepared as part of official government duties for Dr. Pham.  Dr. Pham dedicates this article mentor and friend Jeffrey Fudin, PharmD.

Last updated on: September 8, 2021
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