Analgesics: New This Year to Our Armamentarium

Psychiatric TimesPsychiatric Times Vol 27 No 2
Volume 27
Issue 2

Two new oral analgesics have recently been approved by the FDA: milnacipran (Savella) for fibromyalgia and tapentadol (Nucynta) for moderate to severe acute pain.

Two new oral analgesics have recently been approved by the FDA: milnacipran (Savella) for fibromyalgia and tapentadol (Nucynta) for moderate to severe acute pain.

A new agent for fibromyalgia syndrome

Milnacipran has been available abroad as an antidepressant for several years. Its initial approval in this country is solely as a treatment for fibromyalgia syndrome (FMS). It becomes the third drug to be approved for this disorder: pregabalin (Lyrica) and duloxetine (Cymbalta) were previously approved. Although milnacipran is not approved for the treat-ment of depression in the United States, it carries the same black box warning regarding suicidality among children and young adults as do the antidepressants.

Although some press reports on milnacipran have trumpeted it as the first in a brand new class of drugs, it does not appear to be substantially different from duloxetine in its purported mode of action. Like duloxetine, and also venlafaxine (Effexor), which although not FDA-approved for pain has been demonstrated to have analgesic effects, milnacipran is primarily a serotonin norepinephrine reuptake inhibitor (SNRI). The major difference between these drugs is that while duloxetine is fairly balanced between its effect on these neurotransmitters and venlafaxine is primarily an SSRI at lower doses, milnacipran ratio of effect is 3:1 nor-epinephrine to serotonin reuptake.1,2

The fact that milnacipran provides relief for FMS is not surprising because the drugs that have been shown to be most efficacious for this disorder are the tricyclic antidepressants (TCAs), which are primarily SNRIs. A recent meta-analysis of literature on the use of antidepressants for FMS reinforces this. Of the various categories of antidepressants, TCAs were found to provide more relief for FMS pain than did the other SNRIs, monoamine oxidase inhibitors, or SSRIs. The TCAs also appear to offer more relief for the fatigue and sleep disturbance associated with FMS than do the other classes.3

As with duloxetine and venlafaxine, the major advantage milnacipran has over the TCAs is a more benign adverse-effect profile. Like the other two SNRIs, it lacks the marked anticholinergic and antihistaminic activities of the TCAs.4

Whether milnacipran offers any additional benefits in the treatment of FMS not provided by the TCAs, the other SNRIs, or pregabalin is difficult to answer. There is an unfortunate dearth of research comparing these medications with one another. There is little information on predicting whether one of the antidepressants or the anticonvulsant pregabalin will be more effective for the individual patient with FMS and much less literature that compares the various antidepressants and milnacipran with one another.

A new agent for moderate to severe acute pain

As with milnacipran, tapentadol also bears a strong resemblance to an already existing medication. Tapentadol is a µ-opioid receptor agonist combined with a norepinephrine reuptake inhibitor. Thus, it is similar to tramadol (Ultram)-a µ-opioid receptor agonist combined with an SNRI.

Tapentadol appears to have a much stronger binding affinity for µ-opioid receptors than tramadol. Tapentadol’s binding affinity for these receptors is 1/50 that of morphine; tramadol’s is 1/6000 of morphine. However, as with tramadol, the analgesic effect of tapentadol appears to be more strongly related to its nonopioid action as demonstrated by studies showing that inhibition of the opioid effects of these drugs has much less of an effect on the analgesia they provide than does inhibition of their other actions.5,6 Unlike tramadol, which is not a scheduled drug, tapentadol is a schedule II controlled substance-the same classification as the strongest opioids, including morphine.

One potential difference between tapentadol and tramadol is the risk of seizures associated with each of them. Tramadol appears to increase the risk of seizures even in patients without a history of them. The FDA labeling notes that tapentadol should be “prescribed with care” in patients who have a history of seizures, but there is no listed risk of idiopathic seizures.7 In clinical practice, however, the incidence of idiopathic seizures associated with tramadol appears to be slight.8

What place tapentadol will have in the arsenal of analgesics also remains to be seen. Readers of this column are aware that I have never been a great fan of combination opioids in general or tramadol in particular. My attitude regarding tramadol is that if one wishes to give an opioid and an SNRI, one can prescribe these drugs separately and thus have the ability to adjust the dosage of each independently of the other. Furthermore, the minimal analgesia that appears tobe related to the opioid component of tramadol makes it questionable whether its use warrants the potential risk of abuse or psychological dependence. The stronger opioid effect of tapentadol would suggest that the risk of these problems would be higher with tapentadol than with tramadol.

It will be interesting to see whether tapentadol has any advantages as an analgesic over other oral opioids given either alone or with another drug such as an NSAID, acetaminophen, a TCA, or other SNRI. One reported benefit of tapentadol is that tolerance to it appears to develop more slowly than tolerance to morphine because of its dual mode of action.5 However, considering that it is only FDA-approved for acute pain, tolerance would appear to be much less of an issue than it would be for a drug for chronic pain.

The roles of serotonin and epinephrine in analgesia

The development of milnacipran and tapentadol represents an interesting shift in thinking over the past 20 years regarding the purported roles of serotonin and norepinephrine in analgesia. When the SSRIs were first introduced in the late 1980s, there was a great deal of enthusiasm over their potential benefits as analgesics. The primary school of thought at the time was that it was the serotonergic action of the TCAs that accounted for most of their analgesic effects. However, this view was undermined by studies that found the analgesia provided by SSRIs to be markedly inferior to that offered by the TCAs.

There is one cautionary note to the focus on norepinephrine; all the TCAs, whether they are more serotonergic or noradrenergic, appear to be equally analgesic.




Iyengar S, Webster AA, Hemric-Luecke SK, et al. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.

J Pharmacol Exp Ther.



Kranzler JD, Gendreau JF, Rao SG. The psychopharmacology of fibromyalgia: a drug development perspective.

Psychopharmacol Bull.



Häuser W, Bernardy K, Uçeyler N, et al. Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis.




Savella prescribing information.

. Accessed December 7, 2009.


Tzschentke TM, Christoph T, Kögel B, et al. (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel muopioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.

J Pharmacol Exp Ther.



Tayebi P, Kheirkhah F, Tayebi G, et al. Tramadol effect on morphine dependency and analgesia in mice.

Int J Pharm.



Nucynta prescribing information.

. Accessed December 7, 2009.


Gardner JS, Blough D, Drinkard CR, et al. Trama-dol and seizures: a surveillance study in a managed care population.



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