Introduction
One of the side effects of opioid administration is opioid-induced constipation (OIC), which is reported to occur in 80% of opioid-treated patients and is associated with reduced quality of life (QOL) (Mesía et al., Reference Mesía, Virizuela Echaburu and Gómez2019). To address this side effect, the oral peripheral μ opioid receptor antagonist naldemedine was developed. This drug improves OIC by competitively binding to opioid receptors present in the gastrointestinal tract. In addition, as this drug has a large molecular weight and does not cross the blood–brain barrier, it does not affect the central analgesic effect, and it is thought not to lead to opioid withdrawal syndrome (OWS) with central nervous system symptoms (Katakami et al., Reference Katakami, Harada and Murata2017; Coluzzi et al., Reference Coluzzi, Scerpa and Pergolizzi2020), with similar results obtained for a study on its long-term use (Webster et al., Reference Webster, Nalamachu and Morlion2018).
However, when naldemedine was administered to patients with OIC, cases of OWS were reported shortly after administration (Ishii et al., Reference Ishii, Yamashita and Yamaguchi2020; Ishida et al., Reference Ishida, Hiraoka and Yaguchi2021). Despite this, no findings regarding OWS in relation to long-term administration have been obtained.
Here, we report a cancer patient who presented with symptoms centered on anxiety and irritation 4 months after administration of naldemedine for OIC and who was diagnosed with OWS on the basis of close investigation.
Case report
The patient was a 65-year-old woman who had undergone surgery for stage IB endometrial cancer 4 years previously. She complained of constipation and recurrent tumors were subsequently found in the pelvis by CT 2 years after surgery. She then received extra beam radiotherapy followed by chemotherapy with docetaxel and carboplatin (Nomura et al., Reference Nomura, Aoki and Takahashi2011). However, a disease progression was observed after 11 cycles of chemotherapy. A mass was also found in the mammary gland, which was diagnosed as breast cancer during chemotherapy. In addition, rectal and vaginal fistulas formed due to tumor infiltration, and the patient required to undergo colostomy. Due to overlapping events described above, the patient became depressive and there was a request for consultation at the Department of Psycho-Oncology.
At the first visit, she was found to suffer anxiety about her condition and the artificial anal sphincter, and to feel guilty that she was burdening her family. She had no history of alcohol or drug addiction. She had a calm character and enjoyed strong interpersonal and family relationships. Her psychiatric features fulfilled the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) criteria (American Psychiatric Association, 2013) for adjustment disorder with mixed anxiety and depressed mood.
She received individual and group psychotherapy for patients with recurrent cancer, and her anxiety and guilt were alleviated.
Five months after her initial visit to the Department of Psycho-Oncology, anal pain caused by a pelvic tumor appeared, so the administration of oxycontin (10 mg) was started; however, as the anal pain was not well controlled, tapentadol was added from the 7th month, and naldemedine (0.2 mg) was added as a measure against constipation. In the 8th month, methadone was added, which considerably reduced the pain and improved her level of daily living.
Eleven months after the initial psychiatric examination, she complained that she was more anxious and restless, and that it was difficult for her to wait patiently at the time of her outpatient visits. In addition, symptoms such as fanning of the face due to sudden sweating were also observed. No diarrhea or pain was noted.
At the time, she was receiving tapentadol hydrochloride (200 mg), acetaminophen (1,000 mg), naldemedine (0.2 mg), methadone hydrochloride (30 mg), benfotiamine (100 mg), pyridoxine hydrochloride (100 mg), and cyanocobalamin (1,000 μg).
At first glance, the symptoms were akathisia-like due to the anxiety and restlessness, but she was not receiving any antipsychotic drugs likely to induce akathisia. She had been receiving naldemedine for 4 months and anxiety and sweating were prominent. OWS was suspected based on previous reports of OWS due to naldemedine (Ishii et al., Reference Ishii, Yamashita and Yamaguchi2020; Ishida et al., Reference Ishida, Hiraoka and Yaguchi2021) and it was decided to discontinue naldemedine treatment and follow-up.
At her outpatient visit one week later, all the above symptoms had disappeared. According to the patient, she had symptoms such as restlessness being unable to do anything, not being able to wait patiently at her outpatient consultation, and being unable to concentrate when listening to the doctor in charge the previous, but these symptoms disappeared one or two days after the discontinuation of naldemedine.
Her score on the Clinical Opiate Withdrawal Scale (COWS) (Wesson and Ling, Reference Wesson and Ling2003), improved from 8 points (mild withdrawal) to 0 points (Table 1).
The Clinical Opiate Withdrawal Scale (COWS) before and after discontinuation of naldemedine
Score: 5–12 = mild; 13–24 = moderate; 25–36 = moderately severe; more than 36 = severe withdrawal.
NA, Not Available.
No similar symptoms have recurred during the 6 months since.
Based on the above, the patient was diagnosed with OWS due to naldemedine.
Discussion
Four months after the start of naldemedine treatment for OIC, the patient experienced OWS, with anxiety and irritability as the main symptoms. These findings are very useful in relation to the side effects of naldemedine administration and in the differentiation of anxiety and irritability, which are commonly observed psychological symptoms in cancer patients.
In this case, the patient complained that she was restless and that it was difficult to wait patiently for outpatient consultations, so we considered akathisia as a differential diagnosis (Kawanishi et al., Reference Kawanishi, Onishi and Kato2007). However, the patient was not receiving any psychotropic drugs that might have caused the onset of akathisia, and this diagnosis was contradicted by her sweating, which is rare in akathisia.
A feature of this case was the appearance of withdrawal syndrome 4 months after the start of naldemedine administration. The cases of naldemedine-induced withdrawal syndrome reported to date differed significantly in that the onset of symptoms was observed within 1 h after administration (Ishii et al., Reference Ishii, Yamashita and Yamaguchi2020; Ishida et al., Reference Ishida, Hiraoka and Yaguchi2021). The cause of the appearance of OWS at 4 months after administration of naldemedine is unknown, and future research is required to clarify this.
One limitation to this case report is that no head CT was performed. However, no clinical symptoms suggestive of brain metastasis were observed, and this was true even after 6-months of administration. In addition, no detailed blood tests other than for liver function and renal function were performed. In addition, the resting pulse rate and pupil size required for COWS evaluation were not measured at the time of examination.
Conclusion
We experienced a case of OWS that developed 4 months after the start of naldemedine administration. For patients receiving naldemedine, it is necessary to consider the possibility of OWS regardless of the period of administration in order to maintain patient QOL.
