Refractory pain in a schizophrenic patient on clozapine

Background

Schizophrenia is among the most disabling mental health diseases, ranked among the WHO’s top contributors to the global burden of disease, and is associated with significant functional impairment and stigma.1 Globally, the prevalence of disease ranges between 0.3% and 0.8%.1 In the USA, prevalence estimates are between 0.25% and 0.64% with estimates of potential life lost averaging 28.5 years.2 The economic toll of the disease is similarly significant with annual estimates, in the USA, of about US$63 billion.2–4

With regard to aetiology, genetic and environmental factors, or an interaction of the two, underpin causality.5 The genetic basis of the disease was first established in the 90s in two landmark European twin studies which independently established heritability at about 80% (the authors concluded that environment and or gene–environment interaction among other unknown covariates explained the remainder of disease risk).5 6 In recent years, with advancements in genetic sequencing, GWA studies have proceeded to identify candidate loci: one such large study in 2014 identified over 128 candidate genes—notably, including variants in the DRD2 (dopamine-2-receptor gene), a candidate target of many antipsychotics.7

The neuroanatomic basis of disease has also been investigated. A meta-analysis of voxel-based mophometry studies compared image results of individuals with known elevated risk of disease (HRs), first episode of psychosis (FEP), with controls.8 In that study, differences in the anterior cingulate gyrus were noted with FEP individuals displaying the most grey matter reductions in this region compared with either HRs or controls.8 Furthermore, compared with controls, HRs had decreased grey matter density, further highlighting the importance of this area to disease pathogenesis.8

Patients with schizophrenia typically present with acute psychosis at which point first-line antipsychotics are trialled. However, in a subset of these patients, symptoms persist in spite medication adherence. In this cohort of patients with refractory schizophrenia—often defined as treatment failure in spite trial of two antipsychotics—clozapine is often the drug choice, with its superiority previously validated by multiple landmark Randomized Controlled Trials (RCTs).9 10

Clozapine has multiple well-documented side effects, including agranulocytosis, extrapyramidal symptoms and metabolic dysregulation, myotoxicity among others.11 The myotoxicity of clozapine has been previously demonstrated: in one non-matched cohort study (N=55), elevated CK levels were found in about 13% of all long-term (median of 15 months) clozapine users.12 In that study, a small subset of patients had elevated CK levels (N=2) and were simultaneously symptomatic (reporting muscle weakness and or pain). Furthermore, among those patients, EMG studies found low amplitude motor unit potentials consistent with myopathy.12 Their findings overall provide an organic pathophysiological basis for patients on clozapine reporting nondescript symptoms of pain.

But despite this negative side effect profile, the drug remains favoured as the consequences of lack of treatment in this cohort are dire—there’s a high rate of suicidality among these patients, multiples above the national average.10 As a result of the dire consequences of non-treatment, clinicians routinely monitor and find timely mitigating strategies to minimise the negative impact of these quantitative side effects two times per day to promote adherence to therapy.

Qualitative side effects and their negative impact on adherence, however, are challenging to elucidate and manage. Diffuse body pain is one such example: prevalence data for this side effect are understandably challenging to collect, in part because of the subjective nature of pain.11 13 Other impediments to quantification include communication barriers, both expressive and receptive: on the one hand, schizophrenic patients may fail to coherently describe their symptoms—on the other, provider bias may lead to symptom under-recognition as symptoms are discounted as a representation of a patient’s underlying psychoses14 (interestingly, a high rate of stigmatising attitudes has been documented among medical professionals, even those in mental health15). As a result, the impact of this side effect in treatment adherence and quality of life among schizophrenic patients in the maintenance phase of disease is unclear.

We report our experience with a patient on clozapine who presented with diffuse body pain, bothersome enough that the patient was contemplating discontinuing the medication. After thorough diagnostic evaluation to rule out myopathic or neurological aetiology of the patient’s symptoms, we employed a previously documented intervention of medication readjustment with a positive response. With this intervention, we were able to promote medication adherence and improved quality of life in our patient. To our knowledge, there is only one other documented similar clinical scenario.13 Here, we document a viable framework of approach for providers who may have patients with a similar adverse effect to clozapine.

Case presentation

A 36-year-old patient with a medical history of schizophrenia presented with complaints of diffuse body pain predominantly in the morning. He described the pain as sharp 8/10, diffuse and unbearable and stated that the pain often occurred around the same time each morning. When asked to elaborate further, his descriptions remained vague. Nonetheless, he continually emphasised the debilitating nature of his symptoms, requesting opioids on one occasion.

On further interview, he could not identify any alleviating or palliating factors, although he did repeatedly state that he thought that his medications were the most likely culprit. As a result, he dreaded taking his morning medications and asked, on many occasions, whether his medications could be discontinued.

His physical examination was notably consistently unremarkable with no point tenderness elicited on palpation of the occiput, trapezius, gluteus and greater trochanter muscles. His neurological examination consistently demonstrated 5+ upper and lower extremity strength, negative pronator drift and 2+ deep tendon reflexes throughout.

In terms of medical history, the patient had been diagnosed with schizophrenia (paranoid type) in his 20s and per chart review had had multiple hospitalisations for active suicide attempts. Notably, he had failed trials of initial anti-psychotics including haloperidol and paliperidone. However, a robust response had been noted when he was started on clozapine (he has not had subsequent hospitalisations since commencement of the drug). At the time of presentation, he was stable on a combined 500 mg daily dose (300 mg in the morning and 200 mg at night) with no agranulocytosis on serial surveillance complete blood counts.

Aside from his hospitalisations secondary to schizophrenia, he had no prior hospitalisations or surgeries. The remainder of his history was notable for hyperlipidaemia on atorvastatin 20 mg, hypertriglyceridaemia previously on gemfibrozil 600 mg two times per day and 200 mg two times per day gabapentin for anxiety.

His social history was notable for daily smoking (about one pk each day since the age of 18), and devoid of alcohol or illicit drug use. The patient lived with his mother who is also his designated conservator. No other family members have schizophrenia.

Investigations

Workup revealed a clozapine serum level of 786 (therapeutic per our lab’s assay); normal complete blood count, creatine-kinase (CK) of 55; increased to 65 in 3 months (both normal per our labs assays); triglycerides-275; low density lipoprotein (LDL) of 83 and a normal hepatic panel.

Differential diagnosis

Iatrogenic myopathy, either statin induced or gemfibrozil induced, was the initial leading diagnosis. However, CK levels and liver enzymes consistently remained within normal limits, rendering this diagnosis unlikely. Nonetheless, gemfibrozil was discontinued, while the moderate-intensity statin was continued given the patient’s consistently elevated LDL.

An underlying neuropathy was also considered, however vitamin B₁₂, copper and syphilis testing had all been normal. In addition, no focal weakness had ever been noted on exam. Nonetheless, the patient was trialled on gabapentin (up to 1800 mg daily) without improvement in symptoms.

Fibromyalgia was also considered, however, the patient’s physical examination consistently revealed no tenderness at any major muscle groups.

Intervention

Given the extensive workup done prior, and the lack of response to gabapentin, we queried whether clozapine might be contributory. Clozapine-induced pain had previously been reported elsewhere in a case report that proposed dose-shifting to non-waking hours as a viable solution.13 We thus adopted this strategy of scheduling the bulk of the patient’s clozapine at night-time. At that time, the patient had been taking 500 mg daily split as 300 once a day in the morning and 200 once a day in the evening. We shifted the bulk of his dose to night-time: that is, 100 mg in the morning then 400 mg evening.

Outcome and follow-up

At 1-month follow-up, the patient reported significant improvement in his symptoms, stating that his pain had improved from about an 8–9/10 to 3–4/10 and was overall no longer bothersome to him. As a result, the patient’s entire dose was shifted to night-time with response evaluated later at 3 months and 6 months follow-up. He continued to endorse a similar improvement in symptoms as both these subsequent time points. Furthermore, he remained without psychotic symptoms and was exercising daily.