Efficacy and adverse effects of intravenous lignocaine therapy in fibromyalgia syndrome

Fibromyalgia is a chronic syndrome with widespread continuous muscular pain at rest and tenderness to pressure in at least 11 of 18 specified anatomical sites [1]. It is a common condition with a prevalence in the adult population of 2% [2] and causes considerable disability equivalent to that seen in rheumatoid arthritis [3]. Chronicity is the rule and disability and depression increase with disease duration [4].

Treatments fall into several classes: pharmacological, psychological, physical and complementary therapies. Non-steroidal anti-inflammatory drugs and steroids are unhelpful [5, 6]; tricyclic antidepressants are widely used but their effect is modest [7, 8]. Cognitive behavioural therapies may be useful but are difficult to assess in controlled settings [9]. Electroacupuncture provides only short-term benefit [10], while cardiovascular conditioning has not been adequately studied [11‐13]. Clearly an effective treatment is lacking.

Fibromyalgia is poorly understood in neurobiological terms with no general agreement about its aetiology and pathogenesis. Some authorities contend it is a learned behavioural response to chronic stress [14], whereas others view it in terms of a neuroendocrine abnormality [15]. These two proposed mechanisms may each lead to the other and their manifestations may co-exist.

The symmetry of the condition leads to the hypothesis of a central nervous system disturbance [16]. Pharmacological interference with central pain processing can be achieved in two ways: either by augmenting the action of inhibitory pain pathways or by inhibiting the action of pain pathways. Inhibitory pathway augmentation may be achieved by noradrenergic and serotonergic drugs or by opioids. Pain pathway inhibition may be achieved by systemic administration of local anaesthetics through their inhibition of voltage-gated sodium channels. The effectiveness of the latter, particularly of IV lignocaine, in neuropathic conditions is well established [17, 18]. However, the use of IV lignocaine in fibromyalgia has not been investigated extensively. The effect of a single infusion of 5 mg/kg was investigated in a small number of patients by Sorenson [19]. This demonstrated significant pain relief in some patients for up to five days. A previous open study from our unit evaluated daily lignocaine infusions of 5–7 mg/kg given over 6 days to a small sample of 10 patients [20]; this showed benefit in pain relief and mood scores at 30 day follow up, it did not address duration of pain relief, other quality of life indicators or adverse effects.

The aims of the present studies were (a) to document and quantify any adverse effects of intravenous lignocaine therapy for fibromyalgia patients; (b) to determine if this therapy has benefit upon pain and quality of life; and (c) to measure the duration of benefit.

Fibromyalgia is a chronic syndrome with a variety of symptoms including widespread muscular pain, tenderness, unrefreshed sleep, fatigue and is frequently associated with irritable bowel and bladder symptoms, as well as disability, reduced quality of life and depression [4]. It is defined in terms of pain and tenderness [1] supporting the notion that fibromyalgia is a pain disorder.

Systemic local anaesthetics are primarily prescribed for their antiarrhythmic actions. Short term analgesia is well documented with intravenous lignocaine in a variety of neuropathic pain states such as diabetes [17] and post-herpetic neuralgia [18], and some of these patients appear to derive prolonged relief from such treatment [23].

The mechanism of local anaesthetic infusional therapy is conjectural. There is evidence for disordered sensory processing both at a peripheral and at a central level in fibromyalgia. Sorenson [24] showed by injecting intramuscular saline that there was experimentally induced hyperexcitability in fibromyalgia patients compared with controls. Gibson [25] described hyper-responsive somatosensory evoked potentials (SSEP) to laser skin stimulation and Lorenz [26] showed there was a response to SSEP in both hemispheres compared to controls. The reduced thalamic blood flow seen on SPECT imaging [27] is similar to that encountered in unilateral chronic neuropathic pain using PET [28]. With evidence for disordered pain processing centrally and peripherally in fibromyalgia one can consider it a neuropathic condition providing a rationale for the use of systemic local anaesthetics.

Our data are similar to the other two studies of intravenous lignocaine [19, 20]. Both of these found significant pain relief after treatment, and one of these which measured mood found that this also improved [20]. Other dimensions of pain experience were not measured in these studies.

In the present study the magnitude of effect for pain relief was a 4-point reduction on an 11-point scale; this is likely to be clinically significant. It also fell outside two standard deviations of the average after treatment compared with before, meeting quantitative tests on statistical versus clinical significance [29]. The duration of pain relief averaging 11.5 weeks is also clinically significant; however, the reduction in the number of hours per day in pain fell by only 5 of the 24 hours in the day and suggests that this therapy reduces the severity of pain rather than giving significantly longer pain free periods.

A range of moderately related quality of life measures, that included the psychological and sociological dimension of pain experience, were significantly improved after treatment. Notably, depression, coping, sleep, social life and mobility all improved. The effect of pain upon work did not change. This situation may reflect the socio-economic factors that affect work status which are beyond therapeutic control.

Most of the patients who were sent questionnaires had received this treatment before (37 of the 50 usable replies). It is our clinical practice to not consider repeating this therapy if two sequential treatments are considered ineffective by the patient, thus one might expect a higher proportion of responders to the treatment compared with an unselected group of fibromyalgia patients. However, the results were similar in those who had received this treatment on more than one occasion and in those who had only had the treatment once although the sample for whom this was first treatment was small (n = 13).

The retrospective design used relies upon patient recall. Patients can overrate past pain [30] and thus overestimate benefits of a treatment; however, overestimates seem to particularly occur when pain measures have increased over the treatment period, which was not the case in this study [31]. Pain was our primary endpoint and as a subjective experience is difficult to measure. Rating scales are commonly used for their simplicity and the high associated response rate. We chose to use a numerical rating scale as this compares favourably against visual analogue and verbal rating scales in terms of minimising scoring errors and optimising sensitivity [21].

We included in our questionnaire a range of single questions to cover the dimensions of pain experience: the sensory; affective and cognitive. Many of the multiple-item questionnaires of these dimensions are limited by a complexity that diminishes the number of patients who respond. Our high response rate was achieved with simpler numerical rating scales. Future fibromyalgia research would profit from comparison of these single items with more established measures of quality of life [32]. However, similar single-item scales have been found to have acceptable properties in other pain research [21].

It is difficult to compare our results with other interventional treatments since our population is highly selected having failed these "traditional" therapies such as conventional analgesics, antidepressants and physical therapies. Nevertheless, the outcomes appear clinically significant and all the more so for such a selected population.

We collected data on the use of health care resources since overuse of such resources is a reason for referral. In this area there are no established measures. We used GP visits, which we recognise can involve any interaction, even if the original pain problem is addressed. As such, an unchanged rate of visiting cannot be easily interpreted, but the result we found, of a reduction in GP visits may be meaningful as it indicates that less GP resources were being utilised. However, this treatment has shortcomings from a health resources perspective. Inpatient stay with monitoring by skilled staff and equipment is required which is expensive. Our costs for an episode of treatment are currently 1800 pounds sterling, which we deliver two to three times per year. This expense is potentially justified by the benefits of this treatment demonstrated here.

The prospective study of adverse effects of this therapy demonstrated that side-effects occur and that all of the potentially serious are cardiovascular. Other than the arrhythmia and pulmonary oedema requiring pharmacological treatment, none required an intervention beyond stopping the infusion. Thus cardiovascular monitoring of ECG and heart rate are prudent to prevent more serious sequelae.

Comparison with other studies of our experience with side-effects is difficult because these have not been quantified before. Edwards [23] reported on 221 patients having intravenous lignocaine therapy up to 5 mg/kg for a variety of neuropathic pain conditions. Cardiovascular effects were mentioned as a reason to slow or stop the infusion but no further details were given.

Clearly intravenous lignocaine may cause serious adverse effects and although these appear to be uncommon this must be considered against the fact that fibromyalgia itself is not life-threatening. Against this risk must be set the benefits in terms of symptom relief. In our clinical practice we inform patients of our experience with this therapy in terms of its measured benefits and chances of risks, and most patients elect to try it. Notably, those who have gained symptom improvement despite adverse effects request repeated treatment with intravenous lignocaine. Patients may be best placed to balance the risks and benefits of this therapy after being properly informed.

This study supports the benefits previously described with intravenous lignocaine in fibromyalgia. We have been able to quantify the magnitude and duration of effect, which appears to be clinically significant. The side-effects are common and potentially serious and this therapy should be restricted to specialised hospital sites with close surveillance.

There is a need for a larger study of an unselected patient group and for a controlled study of this therapy to determine confidently its effects and separate the pharmacological effects of lignocaine from more indirect effects of treatment such as inpatient hospital stay and bed rest. It is also necessary to compare this treatment with others used for fibromyalgia such as tricyclic antidepressants.

JHR designed the study, analysed the data and wrote up the manuscript. JLS collected the data. GJT analysed the data. GDK revised the manuscript