Successful Reversal of Opioid-Induced Hyperalgesia and Allodynia with Duloxetine

Dear Editor,

Opioid-induced hyperalgesia (OIH) and allodynia are emerging dilemmas in the management of cancer pain; however, it is mostly considered in postsurgery patients, healthy volunteers, or addicts rather than palliative cancer populations [1]. Patients paradoxically show an increased sensitivity to painful stimuli with increasing doses of opioids, but the mechanism of this is still largely unknown. NMDA receptor antagonists, mu-opioid receptor antagonists, calcium channel ligands, and other treatments are reported to be effective in the short term, yet no definitive consensus has been reached for the treatment of OIH.

We describe a married 58-year-old male diagnosed with “right lung adenocarcinoma” who had worsening pain with increasing oral combinational opioids and did not improve after adding calcium channel ligands. However, the administration of the antidepressant duloxetine, which was prescribed for anxiety and depressive symptoms, effectively controlled OIH. His consumption of opioids decreased gradually in the following three months until his death. Other benefits following the addition of duloxetine included relief of opioid-related adverse events, improvement in the patient’s quality of life, and a decrease in the economic costs of treatment. To our knowledge, no cases of presumed OIH have been previously reported to respond to duloxetine.

The patient had undergone opioid treatment for pain relief discontinuously since 2015. His need for morphine kept increasing over six months, with no significant improvement in pain. The patient began to present exacerbated pain symptoms with general malaise, numbing, burning, stinging, and sensitivity to palpation. The diffuse pain extended from the right ribcage to the whole body. Severe allodynic pain was reported with dressing and light touch. In addition, the patient presented with shortness of breath, facial flushing, sweating, and suicidal ideation. Depression, sleep difficulty, and anxiety symptoms became prominent.

Examination was unremarkable except for CEA 19.11 ng/mL, CA12-5 61.65 U/mL, NSE 12.65 μg/L, CA19-9 9.54 U/mL, and CYFRA 4.89 ng/mL. No deterioration was detected on imaging examination during exacerbating pain. Numerical rating scale (NRS) pain scores fluctuated between 4 and 10. His ID-Pain scale score for neuropathic characteristics was 4 points. Hamilton Depression and Anxiety Scale (HAMD-17, HAMA-14) scores supported the condition of moderate depression and severe anxiety.

Major routine titrated analgesics for duloxetine intervention are listed by month in Table 1. The patient had been off chemotherapy for more than six months. Gabapentin 1.5 g/d and pregabalin 300 mg/d had been used and then ceased to be effective. After psychiatric consultation in April, duloxetine 30 mg/d was added for mood symptoms; six days later, the dosage was increased to 60 mg/d. Duloxetine was increased to 90 mg/d one month later for a relapse of hyperalgesia until his death. Allodynia and hyperalgesia were significantly alleviated about one week after duloxetine intervention. His mood improved quickly, concomitant with pain relief. The requisite dosage of opioids decreased continuously to almost one-third of the original dose at the end of the third month without any additional treatments or improvement of carcinoma.

Table 1

The requirement of opioids in the patient’s last seven months

Month	Jan	Feb	Mar	Apr	May	Jun	Jul
Oxycodone hydrochloride	520	460	220	370	380	230	130
Controlled-release tablets (Oxycontin, 40 mg/tablet)
Morphine sulfate sustained-release	0	170	240	250	210	130	60
Tablets (MS Contin, 30 mg/tablet)
Morphine hydrochloride tablets (30 mg/tablet)	500	1260	1300	1200	740	460	240
Fentanyl transdermal patches (4.2 mg/patch)	0	5	14	0	0	0	0
Morphine equivalent, mg	56,600	79,700	63,800	73,100	58,900	36,100	19,400

The overall equivalent conversion summary of anesthetics is according to the conversion ratio 1:2 of oxycodone and morphine, 4.2 mg: 60 mg of fentanyl transdermal patches and morphine. Records included three months before and four months after intervention.

OIH and allodynia during analgesic treatments were sometimes mistaken for disease deterioration or insufficient titration in the face of presumed opioid tolerance. The latent onset, lack of objective quantitative criteria, individual differences in response to opioids, and comorbidities partially account for the difficulties in confirming the diagnosis of OIH in advanced cancer populations. In this context, OIH should be diagnosed only after ruling out all other possibilities (e.g., chemotherapy induced peripheral neuropathy [CIPN], or diabetes-related peripheral neuropathy [DPN]). Analgesic history and individual symptoms, such as pain sensitization beyond the initial focus, should justify a consideration of OIH. In this case, the rapid relief of OIH without previous specialized treatment suggests that duloxetine (DLX) was therapeutic, and furthermore, the reduction of pain and opioids in the following three months support this presumption.

Recent pathophysiologic research suggests potential mechanisms as to why DLX may help with opioid-induced hyperalgesia. The rapid relief of OIH might rely on the central modulation of tonic descending pain facilitation pathways in the rostral ventromedial medulla (RVM) and blockade of restored antinociceptive potency through changes in activity of NMDA receptors on neurons [2]. As DLX increased the level of noradrenaline in RVM, it may normalize the increased expression of glutamatergic receptor subunit (GluN1) in the glutamatergic system and correct the phosphorylation in NMDA receptors [3]. The continuous analgesic effects of DLX in the long term might rely on neuroimmune modulation. DLX may reduce the overexpression of the TLR4-Myd88-dependent pathway in the spinal dorsal horn in STZ-induced neuropathic pain rats [4]. The role of TLR4 as an emerging therapeutic signaling target mediating anomalous proalgesic actions of opiates and blockade of TLR4 has been shown to facilitate the pain-relieving properties of morphine [5]. Furthermore, DLX may also indirectly act as antiproinflammatory cytokine drug, and its analgesic action requires mu-opioid receptors (MOR) on the primary afferent nociceptors involved in initiating OIH [3].

Anxiety and catastrophizing about pain have been reported as predictive factors of hyperalgesia, particularly in patients taking opioids [6]. However, we note that mood disorders are sometimes ignored in OIH discussions. Although the analgesic effect of DLX has been reported to not fully rely on the effect of mood [7, 8], it still be interesting to consider if negative emotions are involved in enhancing OIH sensitivity. We hope this case highlights the synergistic antalgic effect of duloxetine and stimulates future systematic research into the impact of DLX on presumed OIH.

Conflicts of interest: The authors report no conflicts of interest related to this work.

Acknowledgments

First, thanks to all who suggested improvements. We also acknowledge the patient and his guardian for understanding. Second, this research received grant for publication from Liaoning Provincial Natural Fund Guidance Plan. Project Number 2019-ZD-1024. Third, the authors declared no conflicts of interest in this work. Fourth, this work was approved by the Ethical Committee of the Cancer Hospital of China Medical University. The patient’s guardian has provided written informed consent to have the case details, excluding the patient’s name, published. Fifth, the work described has not been published previously elsewhere in any form.