INTRODUCTION
Akathisia is a common adverse effect of antipsychotics and, less commonly, antidepressants (Khawam et al., Reference Khawam, Laurencic and Malone2006). The clinical picture of akathisia involves subjective complaints of restlessness accompanied by observable restless movements (e.g., fidgety movements of the legs, rocking from foot to foot, pacing, or the inability to sit or stand still) developing within a few weeks of starting or raising the dose of antipsychotics and/or antidepressants (American Psychiatric Association, 1994). The reported prevalence of akathisia has varied between 20% and 75%. Its onset is within a few days of initiation of medication, but it can also occur later in the treatment course (Hsin-Tung & Simpton, Reference Hsin-Tung, Simpson, Sadock and Sadock2000).
Akathisia can cause great discomfort and even agitation and is often described by the patient as the most distressing sensation, and suicide is a reported complication (Shear at al., Reference Shear, Frances and Weiden1983; Atbaşğlu et al., Reference Atbaşğlu, Schultz and Andreasen2001). However, the condition is often underdiagnosed or misdiagnosed as anxiety, agitation, and violent behavior (Siris, Reference Siris1985; Rodgers, Reference Rodgers1992; Hirose, Reference Hirose2003). The reasons for underdiagnosis are considered related to both the patient's symptoms and the clinician's attitude toward akathisia. Patient-related factors include mild degree of akathisia, lack of apparent motor restlessness, lack of clear communication about subjective sensations of restlessness, restlessness in body areas other than the legs, and other clinical signs. Clinician-related factors include overemphasis on objective restlessness, failure to consider akathisia during antipsychotic therapy, and failure to fully implement antiakathisia treatments in ambiguous cases (Hirose, Reference Hirose2003).
There is substantial evidence that tricyclic antidepressants are effective in the management of chronic pain, including cancer pain (Botney & Fields, Reference Botney and Fields1983; Hamon et al., Reference Hamon, Gozlan and Bourgoin1987; Magni et al., Reference Magni, Conlon and Arsie1987). In oncological settings, these agents are used as adjuvant analgesic drugs and are administered along with a primary analgesic, usually an opioid, to treat pain that is refractory to analgesic treatment alone (Portenoy, Reference Portenoy, Doyle, Hanks and MacDonald2001). However, cases of akathisia due to tricyclic antidepressants used as adjuvant analgesic therapy have not previously been reported.
In this communication, we report two advanced cancer patients who developed akathisia due to adjuvant analgesic therapy with tricyclic antidepressants.
To standardize physicians' judgements, Francis' criteria (Francis et al., Reference Francis, Martin and Kapoor1990) were proposed to diagnose akathisia. These criteria are based of a combination of clinical assessment and medical chart review, and the potential cause was categorized as (1) definite, if it was temporally related, there was laboratory confirmation, the patient improved with treatment or cessation of the offending agent, and there was no other cause present or (2) probable, if all the previous criteria were met but another main cause was present or laboratory confirmation was not achieved. In this study, we used the probable criteria because akathisia was confirmed only by clinical observation and careful inquiry, not by laboratory data.
CASE REPORTS
Case 1
A 39-year-old female had been diagnosed as having breast cancer 8 years previously and had received a mastectomy followed by chemotherapy and hormonal therapy. Metastasis of cancer was recognized in the liver and bone and chemotherapy was performed. She developed lumbago that was refractory to nonsteroidal anti-inflammatory drugs and opioids and was thought to be neuropathic in origin. She was administered 75 mg/day of amoxapine, an tricyclic antidepressant, as an adjuvant analgesic therapy. Five months after administration of amoxapine, she suddenly became restless and moved her arms and upper part of the body back and forth. She reported a sensation of inner restlessness in both upper arms, abdomen, and back, but denied such inner restlessness in the lower extremities or legs. Based on this clinical picture, akathisia was suspected, although clinical findings were atypical in that restlessness in the legs was not observed. Amoxapine was discontinued and the inner restlessness was resolved the next day.
The clinical findings and effective alleviation of symptoms after discontinuation of medication fulfilled Francis' criteria for drug-induced akathisia.
Medical history
The patient was a housewife, and had no medical history of psychiatric illness or alcohol or drug abuse. She had a normally cooperative character and was kind to others.
Case 2
A 54-year-old rectal cancer patient developed pain of the left lower thigh. He was treated with 180 mg of loxoprofene sodium, 1.8 mg of fentanyl, and 10 mg of prochlorperazine for about 1 month. As the pain was refractory to conventional therapy and thought to be neuropathic in origin, he was prescribed 10 mg of amoxapine as an adjuvant analgesic therapy. Ten days after administration of amoxapine, he sometimes woke up and walked around the ward slowly, but could not continue because of poor physical condition. He sometimes chewed gum and sucked candies. After careful inquiry, he reported a subjective sensation of inner restlessness in the lower extremities. As akathisia was suspected, prochlorperazine was discontinued first because of the dopamine receptor blockade property of prochlorperazine; however, symptoms of akathisia did not change during the following 2 days. Then amoxapine was discontinued and both motor and inner restlessness were resolved in 2 days. He also stopped chewing gum and sucking candies. The patient explained that he had felt restlessness in the mouth and chewed gum and sucked candies to relieve this sense of inner restlessness.
The clinical findings and effective alleviation of symptoms after discontinuation of medication fulfilled Francis' criteria for drug-induced akathisia.
Medical history
The patient had no medical history of psychiatric illness or alcohol or drug abuse. He had normally cooperative character and was kind to others.
DISCUSSION
Tricyclic antidepressants can be used as adjuvant analgesic drugs. Experimental studies indicate that these drugs potentiate the action of morphine by blocking serotonin reuptake and enhancing the action of serotonin at the spinal terminals of the opioid-mediated intrinsic analgesia system (Botney & Fields, Reference Botney and Fields1983; Hamon et al., Reference Hamon, Gozlan and Bourgoin1987).
These drugs also have extrapyramidal side effects, and amoxapine has been shown to have neuroleptic properties along with antidepressant effects (Krishnan et al., Reference Krishnan, France and Ellinwood1984; Apiquian et al., Reference Apiquian, Fresan and Ulloa2005). It appears that the 7-hydroxy metabolite of amoxapine causes a dopamine receptor blockade (Dolton, Reference Dolton1981).
We reported two cases of akathisia due to tricyclic antidepressants administered for adjuvant analgesic therapy. This is the first report of akathisia induced by adjuvant analgesic therapy using tricyclic antidepressants. Our report suggests that akathisia should be considered a possible side effect during adjuvant analgesic therapy.
In diagnosing akathisia, the typical clinical picture includes inner restlessness and fidgety and restless movement of the body, particularly in the legs. DSM-IV criteria describe restless movements expressed mainly in the legs, and these movements are considered highly characteristic to akathisia (American Psychiatric Association, 1994). However, it has been reported that restless movements may occur in other areas of the body such as arms or abdomen (Ratey & Salzman, Reference Ratey and Salzman1984; Walters et al., Reference Walters, Hening and Chokroverty1989) and may present as dyspnea (Hirose, Reference Hirose2000). It has been reported that leg restlessness is recognized in only 27% (Gibb & Lees, Reference Gibb and Lees1986) and 55% (Sachdev & Kruk, Reference Sachdev and Kruk1994) of the cases.
Case 1 did not report inner restlessness or show restless movements involving the lower extremities or legs. In case 2, restlessness in the mouth has been reported and the patient relieved this sensation in the mouth by chewing gum. And it was difficult to recognize restless movements because the physical condition of the patient was poor and he lay down on the bed almost all day. Although the clinical pictures of akathisia in these patients included atypical features, discontinuation of the suspected drug effectively alleviated symptoms.
Our study suggests that it is important to detect signs and symptoms of akathisia from these subtle combinations of movements. Slow but repeated movements and atypical movements involving areas other than legs together with reports of inner restlessness might be clues to diagnose these patients. The temporal relationships between administration of the drug and the development of symptoms are also important.
Physicians, nurses, pharmacists, and other health professionals should be aware of this possible side effect during adjuvant analgesic therapy. Early detection and appropriate management will improve the quality of life for these patients.
