Will Forte Good Ol Fashioned Opioids

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

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

Background

The management of hurting – whether acute or chronic – is one of the about difficult medical conditions to treat and when treatment options are express, 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 diverse 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 fifty-fifty 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 Over time, some pharmacologic options are withdrawn from the market by the manufacturer, forgotten, or underutilized due to a lack of clinician knowledge or familiarity.

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

Not all pharmacologic handling options are viable for every patient. Here, nosotros revisit the "country of lost analgesics" with the goal of refamiliarizing pain-treating clinicians – whether in specialty or chief intendance – 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 unlike indications and mechanisms of action. Musculus relaxants tin can exist divided into two chief 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.^ane

Orphenadrine citrate

Orphenadrine citrate is classified as an antispasmodic with the mechanism of action being unclear, just is a derivative of diphenhydramine and its activity is believed to be related to its sedative furnishings. In 4 placebo-controlled trials, orphenadrine was plant to exist fairly effective in some musculoskeletal conditions (acute low dorsum hurting, cervix hurting, nocturnal leg cramps) besides as symptoms of pain intensity, stiffness, and functionality.²

However, given orphenadrine'southward chemic nature, information technology 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 every bit 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: astute low dorsum pain, neck pain, nocturnal leg cramps
Bachelor in The states: Yep

Tolperisone

Tolperisone is classified as an antispasmodic with the mechanism of activity possessing lidocaine-similar-activeness 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 exist more effective than placebo for patients with chronic low back pain and overall improvement with short term employ over 21 days, but no reduction of muscle spasms or hurting.¹ Unlike other skeletal musculus relaxants, tolperisone has been shown to exhibit less somnolence or cognitive adverse effects when used with for up to 14 days.³ Equally a skeletal musculus relaxant with less CNS agin effects than currently available in some analgesics, tolperisone may offer a more promising choice for patients.

Brand names: Mydocalm
Formulation: oral
Potential targets: depression back pain
Available in US: No, but the manufacturer is recruiting for Phase three STAR written report nether 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 past 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 musculus wrinkle.¹ ^,2 Dantrolene has shown some efficacy for use in spasticity in debilitating conditions that hinders functionality, merely in that location 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 yet commercially available in oral and injectable formulations and FDA approved for the handling 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 subsequently CNS injury
Available in US: Yes

Meet also, a case report and review of dantrolene for musculus 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 2 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 product to cause vasoconstriction and activate platelet aggregation. COX-two is produced in response to inflammatory and mitogenic stimuli which is important in facilitating inflammation as well as the product of prostacyclin to promote vasodilation and inhibit platelet aggregation.^five

Rofecoxib

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-ii than celecoxib, diclofenac, indomethacin, or meloxicam. As an NSAID with significant COX-ii specificity, rofecoxib has benefits of yielding effective analgesic and anti-inflammatory action with reduced potential for GI-related adverse effects.⁶ Rofecoxib was originally FDA-canonical for the management of acute hurting in adults, primary dysmenorrhea, and osteoarthritis.⁴ ^,half-dozen

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 furnishings compared to celecoxib, ibuprofen, and naproxen with but one trial comparing rofecoxib to celecoxib reporting on the overall rates of GI-related agin events comparing high dose rofecoxib with low dose celecoxib.⁷

In a similar way, 3 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 amongst the full general populations.^vii

In another Cochrane review of 2 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 like a safety contour.The second trial, known as the VIOXX GI Outcomes Research (VIGOR) report,was primarily designed to assess the prophylactic of rofecoxib compared to naproxen which showed like efficacy and lower GI-related adverse furnishings and haemorrhage, only consequently revealed a greater incidental finding of not-fatal myocardial infarctionsin the rofecoxib population.^8,nine

Fortunately, the overall mortality charge per unit and rate of death from cardiovascular causes were similar in the 2 study groups. In another meaning 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 post-obit 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 marketplace in September 2004. Yet, other COX-ii selective NSAIDs such as celecoxib, diclofenac, etodolac, and meloxicam are even so commercially available for clinical utilize.

Brand names: Vioxx
Formulation: oral
Potential targets: osteoarthritis, rheumatoid arthritis, migraine, dysmenorrhea
Available in US: No, merely like products are available as noted above

Benoxaprofen

Benoxaprofen is a arylalkanoic and proprionic acrid derivative NSAID initially FDA-approved for the treatment of osteoarthritis and rheumatoid arthritis. Dissimilar other NSAIDs, benoxaprofen is a weak COX inhibitor, but also has an boosted machinery 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 immune for once daily dosing making it user-friendly for clinicians to prescribe and patients to exist adherent to therapy.^12,13

There was strong consideration that benoxaprofen had disease-modifying furnishings 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 fourteen months was shown effective for continuous antirheumatic stabilization with a unmarried daily dose.¹⁴

Compared to other NSAIDs in rheumatoid arthritis and osteoarthritis, benoxaprofen has been shown to exist 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, in that location was no pregnant deviation in efficacy with rheumatoid arthritis patients.¹²

From an adverse outcome contour, benoxaprofen is somewhat unique as it is associated with low incidences of peripheral edema and peptic ulcers, but has a loftier frequency of phototoxicity and onycholysis.¹² ^, ¹⁴ Photosensitivity typically appears within 48 hours of treatment initiation and resolves 48 hours post-obit discontinuation. Unfortunately, benoxaprofen was voluntarily withdrawn from manufacturer due to cholestatic jaundice with nephrotoxicity and hepatotoxicity. However, benoxaprofen is non unique with respect to its dual activity as a weak inhibitor of COX and its inhibitory furnishings on mononuclear leukocytes every bit sulindac has comparable authority and is even so commercially available for clinical use.¹²

Brand names: Oraflex
Formulation: oral
Potential targets: osteoarthritis, rheumatoid arthritis
Available in Us: Yes

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 backdrop like to aspirin. CMT does non inhibit platelet assemblage induced by two physiological aggregating agents, collagen and arachidonic acid or spontaneous platelet aggregation.¹⁵ The acetyl moiety on aspirin's hydroxyl grouping facilitates it to modify factors of platelet function by irreversible acetylation of COX and thus inhibits the conversion of arachidonic acrid to thromboxane A2 resulting in suppressing platelet aggregation and prolonged bleeding fourth dimension. Dissimilar 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 consequence there is no interference with platelet assemblage or effect on haemorrhage.¹⁶

CMT may be an alternative NSAID for patients prescribed lithium as non-acetylated salicylates may be preferred to minimize gamble for potential drug interactions and inducing lithium toxicity.¹⁷ However, CMT should withal 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-three enzyme inhibitors, vitamin k antagonists, and direct-acting oral anticoagulants.

The virtually 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-canonical for use in the relief of mild to moderate hurting, 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 weather condition.

Brand names: Tricosal, Trilisate
Conception: oral liquid
Potential targets: mild to moderate pain, painful shoulder, pyrexia, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis
Bachelor in Usa: Yes

Zomepirac

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 near equivalent in authorization to indomethacin and tolmetin every bit a COX-one inhibitor of prostaglandin synthesis and was ii or 3 times less active than diclofenac, but more than active than aspirin, ibuprofen, or naproxen.Zomepirac is typically dosed 100 mg every 4 to half-dozen hours as needed, but should not be dosed greater than 400mg/day for three months or longer or exceed 600mg/day every bit these doses have not been studied and are not recommended.^xviii,xix

In looking at the data, zomepirac has demonstrated efficacy in relieving moderate to severe acute postoperative orthopedic, gynecologic, abdominal, and thoracic as well equally dental pain.^18-20 Zomepirac displayed greater efficacy over some opioids and may have been considered a viable selection equally an opioid sparing analgesic. In singe-dose studies in patients with acute hurting, zomepirac 100mg exhibited greater efficacy compared to codeine lx mg as well as other single agent non-opioid analgesics and other analgesic combinations. In unmarried-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 furnishings and suggesting a "ceiling effect" of analgesic activity while also indicating that oral zomepirac was about i-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 unremarkably prescribed NSAIDs such equally 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 half dozen months. Following a unmarried 200-mg dose, zomepirac sodium was shown to prolong the template bleeding time and subtract platelet retention significantly. Dissimilar aspirin and similar to other NSAIDs, zomepirac platelet inhibition is reversible and returns to normal part after 24 to 48 hours following discontinuation of therapy.¹⁸ ^, ^twenty 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 like potency are still commercially bachelor for utilise clinically applicable.

Brand names: Zomax
Formulation: oral
Potential targets: moderate to astringent astute postoperative orthopedic, gynecologic, intestinal, thoracic, and dental pain
Available in The states: No

Adjuvant Analgesics

Neuropathic pain can be i 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 brunt.

Maprotiline

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 activeness as amitriptyline and imipramine, but has a more rapid onset of action and less anticholinergic adverse effects.²¹ ^, ²²

Similar to imipramine, maprotiline exhibits potent norepinephrine reuptake inhibition activity across the nervus jail cell membrane as well equally weak alpha-2 adrenergic blocking activeness. Maprotiline undergoes showtime-pass hepatic metabolism primarily by Due north-demethylation, oxidative deamination, and aliphatic and aromatic hydroxylation to active germination of effluvious methoxy derivatives.²¹ ^, ²² Maprotiline may initiated at 75 mg/solar day and tin can be titrated upward to 225-300mg/mean solar day.²²

In a double-bullheaded 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 proceeds).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/mean solar day if 60 years or older) as tolerated resulted in 72% of patients responding with a greater than a l% 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, simply was not equally effective every bit amitriptyline unless treatment with amitriptyline had failed.²⁵

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

Make names: Ludiomil
Formulation: oral
Potential targets: depressionand feet
Available in US: Aye

More than on the overlap betwixt chronic hurting conditions and psychiatric disorders .

Antiarrhythmics

Mexiletine

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 past blocking voltage-gated sodium channels decreasing the rate of depolarization of ventricular cardiac myocytes, only also has similar dominance in local anesthetic properties.²⁶ ^, ²⁷

Mexiletine is a racemic mixture of R-(–)- and Due south-(+)-enantiomers that possess characteristic antiarrhythmic dominance with the R-(–)-enantiomer exhibiting increased cardiac sodium aqueduct bounden and greater antiarrhythmic activity than the S-(+)-enantiomer, just neither of the isomers significantly changed the electrocardiographic intervals (PR, QRS, QTc) or refractory periods.²⁶ Mexiletine has been used to care for various neuropathic pain syndromes including: alcoholic neuropathy, cancer and radiations-induced neuropathic pain, painful diabetic neuropathy, dysaesthetic hurting associated with multiple sclerosis, HIV-induced neuropathy, myofascial hurting, peripheral nervus affliction, phantom limb hurting, postherpetic neuralgia, spinal cord injury, thalamic (mail-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 agin effects.²⁶ Notwithstanding, in that location are no serum mexiletine concentration levels that correlate with efficacy in relieving neuropathic pain syndromes that accept been studied. Therapeutic doses of mexiletine have ranged from 300 to 675mg/day, but clinicians should be vigilant and avoid dosages that can upshot in serum concentrations exceeding >ii mg/Fifty. 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, just should be used with caution and monitored closely during initiation and dose titrations peculiarly in the setting of potential clinically pregnant drug-drug interactions.²⁶ ^, ²⁸

Opioids may take a potential clinically significant drug interaction with mexiletine. Despite at that place being no studies designed to evaluate the furnishings of opioids on the pharmacokinetics of mexiletine, information technology has been reported that patients taking morphine take significantly lower mean concentrations of mexiletine 3 hours post-obit the first dose. The machinery 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 beneath.)

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

Make names: Mexitil
Formulation: oral
Potential targets: neuropathic pain
Available in Us: Yes

Opioids

Opioids are not merely purely mu-opioid agonists; some can exist mixedmu opioid receptor agonist-antagonists, as well equally agonists of the delta and or kappa opioid receptors with varying pharmacodynamic effects. Mixedmu opioid receptor agonist-antagonists are not used equally often as total mu-opioid agonists due to their limited commercial availability, but every bit a outcome of their antagonist activeness has less dependence and abuse potential.

Opioid analgesics may be considered as adjunctive therapy upon initiation and during optimization of not-opioid analgesics peculiarly 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 every bit overall pain improves with optimization of non-opioid analgesics. If opioids are to be used, adventure mitigation strategies such as obtaining an opioid treatment understanding or consent, review of prescription drug monitoring programme reports, and conducting urine drug testing should be performed periodically as clinically indicated every bit recommended per established clinical practice guidelines every bit well as state regulations.

Butorphanol

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 say-so of parental butorphanol ranges from four to 8 times more than morphine, 30 to 40 times more than than meperidine, and 15 to 24 times more than pentazocine whereas oral is almost 7 times more codeine and 6 times more than pentazocine.²⁹ ^, ³⁰

Butorphanol'southward antagonist activity is about xxx times more than pentazocine while only a fraction (1/40) of naloxone and given its loftier binding analogousness to the mu opioid receptor, higher doses of naloxone may exist necessary in social club to contrary whatsoever agin effects of butorphanol compared to pure opioid agonists such every bit 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 small metabolite norbutorphanol which leaves oral bioavailability yielding most but 5 to 17%. With transnasal administration of butorphanol on the other hand, this road of assistants bypasses the gastrointestinal tract, and improving bioavailability to about 48 to seventy% like to parenteral administration.³⁰

Additionally, transnasal butorphanol absorbs chop-chop while providing onset of analgesia within fifteen minutes making information technology an ideal brusk-term treatment option for patients with moderate to severe astute postoperative, musculoskeletal and migraine headache hurting. The bioavailability and pharmacokinetics of transnasal butorphanol may be influenced by age and sexual activity as the median value for t_max 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 C_max and AUC values were relatively similar.³⁰

The most mutual agin effects to be expected from butorphanol are sedation, drowsiness, dizziness, as well as nausea and/or airsickness. Dissimilar pure opioid agonists such equally morphine which can crusade respiratory depression in a dose proportional manner, butorphanol exhibits a 'ceiling effect' with respect to the caste of respiratory depression such as increasing doses across 2mg may not outcome in a corresponding increment in degree of respiratory depression, but the duration of respiratory depression increases with higher doses.²⁹ ^, ³⁰Butorphanol has hemodynamic effects similar to pentazocine but to a lesser degree with cardiovascular furnishings consisting of: increased pulmonary artery and wedge pressure, increased left ventricular cease diastolic pressure, increased systemic arterial pressure, increased pulmonary vascular resistance, likewise as increases to cardiac index and cardiac work.²⁹

Considering these cardiovascular furnishings, 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, every bit 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 hurting, postpartum pain, perioperative
Bachelor in US: Yes (generic); Stadol (US) was discontinued due to severe hypertension

Nalbuphine

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.vii to 0.8 times that of morphine whereas oral is 3 times more than codeine.²⁹ ^, ³²

In comparing to pentazocine, nalbuphine is near 3 to 4 times more than stiff with a longer duration of activeness and 10 times more constructive with its antagonist activity.²⁹ ^,3 ¹ Like to butorphanol, nalbuphine exhibits sufficient absorption via oral and parenteral routes, but undergoes extensive first-pass hepatic metabolism with oral bioavailability yielding simply nearly 20%.²⁹

Much similar any other opioid, the most common adverse furnishings exhibited with nalbuphine include sedation, drowsiness, dizziness, as well every bit nausea and/or airsickness.²⁹ Comparable to butorphanol, nalbuphine besides exhibits a "ceiling result", just to both the caste and duration of respiratory depression as escalating doses does not prolong the duration of respiratory depression across 3 hours regardless of dose and thus resulting in a plateau of the respiratory depression curve.²⁹ ^, ³¹ ^, ³² In a report comparing nalbuphine and morphine in patients with astute 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 residuum betwixt myocardial oxygen supply and demand.²⁹

Nalbuphine's cardiovascular benefits with decreasing middle charge per unit and contractility while maintaining aortic perfusion force per unit area may prevent further cardiac ischemia in patients with acute myocardial infarction. Nalbuphine is FDA-approved for use every bit an analgesic for moderate to severe pain, for preoperative analgesia, as a supplement to surgical anesthesia, and every bit obstetrical analgesia during labor.²⁹

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

Propoxyphene

Propoxyphene is a constructed diphenyl heptane mu opioid receptor agonist, kappa opioid receptor agonist, and noncompetitive N-methyl-D-aspartate (NMDA) receptor antagoniststructurally like to methadone that has two centers of disproportion and exists as four stereoisomers: alpha-dextrorotatory isomer, blastoff-levorotatory isomer, dextropropoxyphene, and levopropoxyphene. Dextropropoxyphene exhibits analgesic activity and levopropoxyphene has antitussive activity while the other levorotatory isomers are relatively inactive, simply overall none of the isomers tin can be converted into methadone.Propoxyphene is about 33.33% to 50% the authorisation 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 well-nigh only 18-25% from a 65mg dose.Propoxyphene is both a CYP450 2D6 inhibitor and substrate and consequently may be subjected to genetic polymorphisms equally well equally potential drug interactions.^33,34

In a review written by Miller and colleagues, amid 243 manufactures referencing propoxyphene, merely 20 double-blind or triple-bullheaded 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 aforementioned parameters no study demonstrated that codeine was junior 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

Non all of the comparison studies reviewed presented propoxyphene as inferior every bit 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 information technology was non.³⁵

Mutual adverse furnishings with propoxyphene are similar to other opioids which include: dizziness, lightheadedness, visual disturbances, somnolence, drowsiness, seizures, euphoria, nausea, vomiting, abdominal hurting, constipation, urinary memory. 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 straight cardiac agin effects which include: an increase in bradycardia, decreased contractility, decreased electric conductivity, QTc interval prolongation, besides as local anesthetic backdrop like 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-gamble patients and at loftier doses.Prior to removal, propoxyphene was falling out of favor by clinicians and was perceived to have no therapeutic do good in the management of acute and/or chronic pain while having greater bloodshed risk due to its cardiac and neurologic toxicity profile.³⁴

In 2009, the FDA required the drug manufacturer to behave a multiple-ascending dose (MAD) study which was a randomized, double-blind, placebo-controlled sequential multiple-ascending dose report of propoxyphene for eleven days evaluating 600 mg and 900 mg cohorts.The results of the MAD study were submitted to the FDA past 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 confronting its apply 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 subsequently due to the FDA'southward cardiotoxicity alert. Other short-interim firsthand-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)
Conception: oral
Potential targets: breakthrough pain
Available in US: No, but similar products are still available

Levorphanol

Levorphanol has been referred to every bit the "forgotten opioid" that is phenanthrene mu, delta, and kappa opioid receptor agonist and not-competitive NMDA receptor antagonist structurally similar to morphine, but without an oxygen and a 6-hydroxyl group.^37-39Similar to morphine, levorphanol has anticholinergic effects and like methadone, levorphanol inhibits the uptake of serotonin and norepinephrine.³⁸ Still, 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 skilful absorption through the intramuscular, subcutaneous, and oral routes of assistants 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 feasible option and may crave a lesser need for coadministration of adjuvant analgesics.³⁷

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

Brand names: Levo-Dromoran
Formulation: oral
Potential targets: severe hurting
Available in US: Yep

Clinical Takeaways

Pharmacologic options of the past for treating astute, 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 yet available and simply remain forgotten or underutilized. Pain practitioners beyond specialties are encouraged to refamiliarize themselves with these drugs in case they may benefit a detail patient who is refractory to or contraindicated for more widely used products.

Non all pharmacologic treatment options, however, are viable for every case; as with any prescription, risks and benefits must be weighed. Having a fuller, fifty-fifty if older, armory of potential treatment modalities for pain management can simply serve to do good the clinician and the patient. All pharmacologic handling options old and new should be reconsidered based within patient-specific clinical parameters and trialed as potential culling analgesics where possible.

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

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

Last updated on: September 8, 2021