Fibrous myopathy induced by intramuscular injections of cyclizine
- 1 Manchester Medical School, The University of Manchester Faculty of Biology Medicine and Health, Manchester, UK
- 2 Department of Neuropathology, Greater Manchester Neurosciences Centre, Salford, UK
- 3 Centre for Musculoskeletal Research, The University of Manchester Faculty of Biology Medicine and Health, Manchester, UK
- Correspondence to Rory James Tinker; rorytinker2011@gmail.com
Abstract
A 63-year-old woman was referred to neurology with bilateral severe progressive pain and stiffness in her thighs. The patient had a 3-year history of injecting intramuscular cyclizine into the anterior thigh to treat nausea associated with a longstanding pan-enteric dysmotility syndrome. MRI of the thighs demonstrated fibrotic appearances. A biopsy of the left vastus lateralis and surrounding fascia identified pathology consistent with a fibrous myopathy. The patient was advised to stop intramuscular injections of cyclizine and undergo physiotherapy but she still remained in considerable pain. Although fibrous myopathy occurring as a consequence of recurrent intramuscular drug injections, particularly heroin, has been previously described, this is the first report of fibrous myopathy associated with the use of intramuscular cyclizine. We highlight this rare association and suggest that the long-term use of intramuscular cyclizine be avoided.
Background
Cyclizine is an H1-receptor antagonist (antihistamine) used to treat and prevent nausea, vomiting and dizziness.1 It can be administered orally, as a suppository, or by intravenous or intramuscular injection.1 Common side effects include drowsiness, xerostomia, constipation, hypotension and urinary retention.2 A benefit of intramuscular injection is that due to the large vascular supply of skeletal muscle, especially in comparison with subcutaneous tissue, there is a higher rate of absorption.3 4 Complications of intramuscular injections are rare but can include hematoma formation, aseptic tissue necrosis, nerve injury, cellulitis and infective myositis.4 In addition, certain medicinal agents can trigger secondary pathology, including a fibrous myopathy.5
Fibrous myopathy is a subtype of the toxic myopathies.6 7 These disorders involve an acute or subacute myopathic syndrome, generally occurring in patients without pre-existing muscle disease, after exposure to certain drugs.6 The most common medication-induced toxic myopathy is statin-related myotoxicity. In fibrous myopathy, normal tissue is replaced by fibrous connective tissue and can be triggered by recurrent intramuscular injections of medicinal agents or illicit drugs, particularly heroin.8 9 The condition usually presents with a painless, fibrous, hard and indurated muscle which is stiff in both active and passive movement.8 9 Serum creatine kinase and electromyography are normal.8 9 Ultrasound imaging usually demonstrates an enlargement of muscle structure with thickened connective tissue.8 9 On biopsy, muscle fibres may show abnormal variation in size and replacement by endomysial connective tissue.8 9 Fibrous myopathy has been previously treated with a suspension of the causative intramuscular injection, administration of prednisone or penicillamine, and physical therapy.8 9 Here we highlight the first reported case of fibrous myopathy associated with long-term use of intramuscular cyclizine.
CASE PRESENTATION
A 63-year-old woman was referred to an outpatient neurology clinic at a tertiary neurosciences centre in the
Northwest of England. For the previous 3 years, the patient had been injecting intramuscular cyclizine to treat nausea associated with pan-enteric dysmotility syndrome. Initially, the patient injected into the deltoids but switched to the anterior thigh after these sites became painful. The patient injected intramuscular cyclizine three times a day for 3 years. This resulted in approximately 3285 injections. The patient subsequently developed bilateral progressive generalised hip and thigh pain, evolving over a 12-month period. The pain was eased by non-steroidal anti-inflammatory medication and was associated with bilateral weakness, stiffness and cramping in her thighs, shoulder and calves.
The patient had initially presented to orthopaedics after a right displaced intracapsular neck of femur fracture sustained during a fall down the stairs. The orthopaedists noted that the pain and associated symptoms were unrelated to the hip displacement, especially as they had been present and progressing before the fracture occurred.
The patient had an extensive medical history including coeliac disease, generalised intestinal dysmotility syndrome, anxiety, depression, stress incontinence and L5/S1 degenerative disk disease without compression of spinal cord or nerve roots. Surgically, the patient had previously undergone a subtotal colectomy and small bowel resection to treat slow transit constipation, an appendectomy, a cholecystectomy to treat gall stones and a bladder prolapse repair.
On examination, the patient’s thighs appeared bruised and both knees had a 70-degree fixed flexion deformity. There was significant stiffness of the quadriceps muscles bilaterally. On neurological examination, the patient had an antalgic gait and was mobilising with two crutches due to the significant pain and stiffness over the thigh muscle. There was limited power in hip flexion. Otherwise, the rest of the neurological examination (cranial nerves, upper and lower limbs) was normal.
Differentials and investigations
The differential list considered for the patient is presented in table 1.
The major differentials for subacute progressive thigh pain and weakness21–24
| Differential | Factors reducing diagnostic probability in this case |
| Avascular necrosis of hip fracture | MRI demonstrated no hip fracture pathology |
| Polymyalgia rheumatic | Normal inflammatory markers |
| Inflammatory myopathy | Normal inflammatory markers and creatine kinase |
| Mixed connective tissue disease | Negative antibody screen |
Routine blood tests including serum total creatine kinase and inflammatory markers were normal. A myositis antiextractable nuclear antigen autoantibody screen was negative. An MRI scan of the hips and thighs was reviewed which demonstrated extensive bilateral fibrous myopathic changes in the anterolateral thighs (figure 1).
MRI (T1 (A–C) and short-TI inversion recovery (D–F)) demonstrating extensive fibrous myopathic changes bilateral in the anterolateral thighs.
This raised the diagnostic probability of a toxic myopathy and thus a left vastus lateralis muscle biopsy was performed to investigate further. This showed extensive replacement of muscle by marked perimysial and endomysial sclerosis accompanied by limited, focal perivascular lymphocytic cuffing by T lymphocytes with no evidence of vasculopathy including vasculitis or macrophage activity (figure 2). The histology was consistent with a fibrous myopathy due to recurrent injection of a medicinal agent into the thigh muscles.
Biopsy of the left vastus lateralis muscle demonstrating marked fibrosis of endomysium and perimysium, severe loss of myofibres and moderately severe to severe atrophy of residual myofibres (H&E stain, original magnification ×50).
Treatment
The patient was managed with a multidisciplinary approach. The intramuscular cyclizine injections were suspended and substituted for oral ondansetron. However, this failed to adequately control her nausea and she was subsequently offered subcutaneous levomepromazine. Pain management specialists increased the oral morphine dose and counselled her on pain self-management. Furthermore, the patient was referred to physiotherapy for global lower limb exercises with a view to increasing exercise tolerance and strength. An occupational therapist assessed the patient’s home for adaptation considering her potential long-term reduction in musculoskeletal strength.
Outcome and follow-up
Unfortunately, the patient declined subcutaneous levomepromazine to control her nausea because of concerns relating to the possible increased thrombotic risk associated with this medication. At her discretion, the patient elected to continue to inject intramuscular cyclizine but was encouraged to vary injection sites as much as possible.
Discussion
This case demonstrates the extensive replacement of normal muscle tissue with fibrous connective tissue in a patient using long-term intramuscular cyclizine injected into the same area. The development of fibrous myopathy substantially reduced the functional abilities of the patient. This resulted in further disability in addition to the suffering already associated with her chronic nausea.
Fibrous myopathy has previously been reported in both painful and painless forms.10–17 Several medications have been reported as potential causes of fibrous myopathy when used intramuscularly, including pentazocine, butorphanol, propoxyphene, heroin, piritramide, methadone and meperidine.10–17 It is unclear if fibrous myopathy is the result of repeated needle-related muscle trauma or the myotoxic properties of the injected agents. The difference in pharmacokinetic properties between cyclizine and the narcotic analgesics adds further complexity to ascertaining the pathological mechanism. Intramuscular injection of cyclizine contains lactic acid and water as excipients and has a pH in the range of 3.3–3.7.18 Chronic damage to muscle as a result of repeated mechanical injury, as well as the acidic pH of the injected material, are both likely to contribute to the dysfunctional and uncoordinated muscular repair and fibrous replacement of muscle tissue seen in our patient.19
There are uncertainties as to whether the risk of developing fibrous myopathy derives from the total number of injections, the dose of each injection, or the frequency of injections. Investigation of how these factors contribute to the pathology in fibrous myopathy could be a focus of future research. In the case reported here, the patient injected intramuscular cyclizine three times a day for 3 years, resulting in approximately 3285 injections. Although fibrous myopathy has also been shown to occur in patients with fewer injections, the range varies widely between 100s and 10 000s.14-21
There is a paucity of robust evidence in the literature to support any particular therapeutic strategy or prognostic factors. There are also uncertainties regarding the potential reversibility of fibrous myopathy. In the case reported here, the symptoms did not resolve or improve after the cessation of intramuscular injections for 6 months and the muscle imaging demonstrated significant muscle damage. However, it has previously been reported that fibrous myopathy (after 500 injections of intramuscular heroin) was reversible after suspension of intramuscular injections and administration of glucocorticoids and penicillamine. 16 It is possible that the relatively lower number of intramuscular injections in this previous report contributed to the reversibility observed. Although it could be postulated that increasing levels of muscle fibrosis are associated with a lower capacity for recovery and a poorer outcome, the exact relationship between the severity of the pathology and prognosis is poorly understood. The establishment of an international cohort of patients with fibrous myopathy could provide an opportunity to understand the factors associated with prognosis in standardised fashion. The lack of literature in fibrous myopathy contrasts with Duchenne muscular dystrophy, where muscle fibrosis has negative prognostic implications.20 This is likely due to fibrosis preventing regeneration of endogenous myogenic cells, impeding the delivery of cell-based therapeutic agents to affected tissue.20
In light of this case, we suggest that intramuscular cyclizine should be avoided if long-term treatment is required, particularly if variable injection sites are not able to be used. If there is no reasonable alternative, then clinicians and patients should have a low threshold for considering the development of fibrous myopathy so that the injections can be stopped before permanent damage to muscle occurs.
Learning points
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Fibrous myopathy is a reported consequence of the intramuscular injection of analgesics and now cyclizine.
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Fibrous myopathy can lead to significant morbidity.
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A multidisciplinary team approach is needed to investigate and treat patients presenting with symptoms of fibrous myopathy.
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Further research is required to identify the mechanism of how intramuscular injections of certain medications result in fibrous myopathy.
Footnotes
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Twitter @rozatinker
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Contributors RJT: preparation of manuscript, editing, literature search. RW: preparation of manuscript. DdP: histology. JBL: preparation of manuscript, editing, patient care.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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