Duloxetine in the Treatment of Chronic Pain: A brief overview

David Nauen, Family Medicine Clerkship, December 2008

Mechanisms of chronic pain

Most clinically signicant causes of chronic pain are likely to

begin with damage to peripheral sensory nerve bers. The
loss of small, unmyelinated pain bers leads to loss of sensation for thermal and mechanical noxious stimuli. When
myelinated bers are aected, light touch, vibration sensation, and two-point discrimination are decreased. Paresthesias and pain can follow the loss of sensory bers, and allodynia, perception of normally benign stimuli as noxious, is also
seen. Chronic pain is widely thought to be due to central sensitization of pain receptive systems (Woolf and Manion, 1999)
following sensory loss.
The involvement of central serotonergic neurons in pain perception was supported by experiments with a conditional
knockout that lacked these neurons; SSRI-mediated analgesia was greatly reduced (Zhao et al., 2007). The primary somatosensory cortex may contribute more than other brain areas to one laboratory proxy for chronic pain, thermal hyperalgesia: SSRI-mediated relief of this form of sensitivity was
seen with injection into primary somatosensory cortex, while
injection into cingulate or basolateral amygdala had no eect
(Matsuzawa-Yanagida et al., 2008).
Descending axons from cortex, hypothalamus and amygdala
synapse onto neurons in the periaqueductal gray, the rostroventral medulla, and the dorsolateral pontomesencephalic
tegmentum, the latter two of which project to the dorsal horn
of the spinal cord (Iyengar et al., 2004). Both serotonergic
and noradrenergic systems are involved (Fields and Basbaum,
1999).
Depression is often linked with chronic pain, both as a cause
and an eect . In a study of 19,000 patients, 43% of those diagnosed with major depressive disorder experienced at least
one comorbid symptom of pain and discomfort (Simon et
al., 1999). Another frequent cause of pain is diabetes mellitus. DM is associated with peripheral neuropathy in approximately one-third of patients (Ziegler 2008), and neuropathic
pain is present in 8-26% of diabetic patients (Ziegler et al.,
2008, Daousi et al., 2004, Davies et al., 2006).
Blocking reuptake of serotonin and norepinephrine can have
a greater analgesic eect than the sum of each agents activities when acting alone (Figure 1, Iyengar et al., 2004). This
synergistic eect (Zhuo and Gephart, 1997) suggests that the
two transmitters participate in distinct components of the
pain circuitry.
Interesting implications for mechanisms of chronic pain were
obtained by study of response to intrathecal antidepressants
in two rodent models of pain (Ikeda et al., 2008). Streptozocin (STZ)-induced insulin-dependent diabetes leads to increased sensitivity and allodynia. Chronic constriction injury
(CCI) generated by applying cus to the sciatic nerve has
similar results. For CCI, however, the SSNRI milnacipram
(Mochizuki 2004) markedly increased the pain withdrawal
threshold, while paroxetine and uvoxamine had essentially
no eect (Figure 2A), whereas for STZ, both classes of drugs
had a pronounced eect (Figure 2B). This suggests that the

Figure 1: The eect of SNRI and SSRI together is greater

than the sum of their individual eects. From Iyengar et al.,
2004.
mechanisms of pain in diabetic neuropathy may dier from
those at work when compression (e.g., disc herniation) leads
to chronic pain.

Figure 2: SSNRI, but not SSRI, is eective for compression pain (A), while either class is eective for hyperglycemiainduced pain (B). From Ikeda et al., 2008.

Characteristics,
pharmacodynamics, and pharmacokinetics of
duloxetine

Duloxetine (Figure 3, Wong et al., 1993) is classed as a selective serotonin-norepinephrine reuptake inhibitor. In vivo it
was as eective at blocking para-chloramphetamine-induced
depletion of serotonin as was paroxetine, while it was as eective at blocking depletion of norephinerphrine in -methylm-tyrosine treated rats as was desipramine (Iyengar et al.,
2004). It has very low or no anity for muscarinic, histamine1, 1 -adrenergic, dopamine, opioid, or 5-HT1A, 1B, 1D, 2A,
1

In summary, neuropathic pain is likely to involve central sensitization after damage to peripheral sensory nerves. The
mechanisms of pain due to diabetic neuropathy may differ from those set in motion by constriction injury. Both
serotonin- and norepinephrine-mediated synaptic transmission can contribute to chronic pain, likely by working in nonredundant components of the pain circuit. Duloxetine, an antagonist of both serotonin and norepinephrine transporters,
appears to be an eective remedy for chronic neuropathic
pain such as that caused by diabetic neuropathy. In vitro,
animal, and clinical studies of the compound have improved
our understanding of the mechanisms of chronic neuropathic
pain. It is to be hoped that with increasingly widespread use
the compound will continue to present no evidence of significant toxicity or long-term safety concerns.

and 2C receptors (Bymaster et al., 2001).

Its many phase I metabolites and phase II glucuronide and
sulfate conjugates are minimally active (Kuo et al., 2004).
Maximal plasma concentrations are reached after about 6
hours, and the half life is roughly 12 hours. Eective volume of distribution is 1640 L as duloxetine is highly plasma
bound. Hepatic metabolism is by the cytochrome P-450 enzymes 1A2 (interaction with uvoxamine, cimetidine, uoroquinolones) and 2D6 (interaction with paroxetine, uoxetine,
quinidine; duloxetine will increase serum concentrations of
TCAs, pheonthiazines, and type 1c anti-arrhythmics; Smith
and Nicholson, 2007).

References

Bymaster F. et al. Comparative anity of duloxetine and venlafaxine for

serotonin and norepinephrine transporters in vitro and in vivo, human
serotonin receptor subtypes and other neuronal receptors. Neuropsychopharmacology, 25:871-880.
Daousi C. et al. Chronic painful peripheral neuropathy in an urban
community: a controlled comparison of people with and without diabetes.
Diabetes Medicine 2004, 21:976-982.

Figure 3: The structure of duloxetine. From Smith and

Nicholson, 2007.

Davies M. et al. The prevalence, severity and impact of painful diabetic

neuropathy in Type 2 diabetes. Diabetes Care 2006, 29:1518-1522.

Eectiveness of duloxetine for

chronic pain

Fields H. and Basbaum A. Central nervous system mechanisms of pain

modulation, in Textbook of Pain, 4th edition (Wall and Melzack, editors),
309-329.

A review by Smith and Nicholson (2007) of 3 clinical studies

of duloxetine provides information on its eectiveness1 :

Ikeda T. et al. Eects of intrathecal administration of newer antidepressants

on mechanical allodynia in rat models of neuropathic pain. Neuroscience
Research, in press.

The average response to duloxetine at 60 mg/day

was 47.2% of patients getting 50% reduction
in pain, with 27.9% having this degree of response
with placebo. 60 or 120 mg daily were signicantly dierent from placebo in 24-hour average
pain score within 1 week of onset of treatment and
increasingly for all weeks thereafter. Both doses
also resulted in signicant reductions in 24-hour
worst pain and night pain, as well as brief pain index severity. The 60 mg qd dose was almost identical to placebo in percentage of patients discontinuing during the 12 weeks of the studies. Morover, the
95% CI for 60 mg daily did not overlap with that
of placebo on the indices of clinicians global impression, short form McGill pain questionaire, and
dynamic allodynia. Surprisingly, the Hamilton depression score actually increased versus placebo for
patients on 120 mg/day. The higher dose was also
associated with worse side eects including nausea, somnolence, dizziness, constipation, and fatigue, though at 60 mg these were worse than with
placebo. [Paraphrased.]

Iyengar S. et al. Ecacy of duloxetine, a potent and balanced serotoninnorepinephrine reuptake inhibotor in persistent pain models in rats. Journal
of Pharmacology and Experimental Therapeutics 2004, 311:576-584.
Kuo F., et al. Synthesis and biological activity of some known and putative
duloxetine metabolites. Bioorganic and Medicinal Chemistry Letters 2004,
14:3481-3486.
Matsuzawa-Yanagida K. et al. Usefulness of antidepressants for improving
the neuropathic pain-like state and pain-induced anxieity through actions at
dierent brain sites. Neuropsychopharmacology 2008, 33:1952-1965.
Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal
models of pain. Human Psychopharmacology 2004, 19:S15-S19.
Simon G. et al. An international study of the relation between somatic
symptoms and depression. New England Journal of Medicine 1999, 341:13291335.
Wong D. et al. LY248686, a new inhibitor of serotonin and norepinephrine
reuptake. Neuropsychopharmacology 1993, 8:23-33.
Woolf D. and Mannion R. Neuropathic pain: aetiology, symptoms, mechanisms and management. Lancet 353:1959-1964.
Zhao Z. et al. Mice lacking central serotonergic neurons show enhanced
inammatory pain and an impaired analgesic response to antidepressant
drugs. Journal of Neuroscience 2007, 27:6045-6053.

Duloxetine had little eect on acute nociception (Iyengar

et al., 2004), suggesting that it may work at levels above the
spinal cord, or on pain pathways only activated by persistent
pain. The reduced eectiveness of SSRIs seen with knockout
of central serotinergic neurons was also seen with duloxetine
(Zhao et al., 2007), indicating that its mechanism of action
involves changes in central serotonin transmission.

Zhuo M. and Gephardt G. Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat. Journal of Neurophysiology
78:746-758.
Ziegler D. Painful diabetic neuropathy: treatment and future aspects.
Diabetes/Metabolism Research and Reviews 2008, 24(Supplement 1):S52-S57.
Ziegler D. et al. Prevalence of polyneuropathy in prediabetes is associated
with abdominal obesity and macroangiopathy: the MONICA/KORA
Augsburg Surveys S2 and S3. Diabetes Care 2008, 31:464-469.

1 It bears noting, however, that their article contains no Conict of Interest disclosure.