Definition

The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) defines critical limb ischaemia (CLI) as the following: any patient with chronic ischaemic rest pain, ulcers or gangrene attributable to objectively proven arterial occlusive disease.1 CLI is a chronic condition, distinct from acute limb ischaemia.

CLI is a severe stage of peripheral arterial disease. Patients with CLI can be classified in the grades of the Fontaine classification (stages III–IV) or the Rutherford classification (grades 4–6). Not all patients progress through the predefined stages from claudication to CLI.2 Progression to CLI is often variable and unpredictable.

Epidemiology

CLI will develop in 500–1000 patients annually in a Western population of 1 million people.1 It is associated with surgery, hospitalisation and death.3 Patients with CLI have cardiovascular event rates higher than those in patients with symptomatic coronary artery disease.4 Thomas et al found that in patients with conservatively treated severe CLI, all-cause mortality was 58% with a 2-year survivability rate of 55%.5 The 5-year mortality exceeds that of colorectal cancer, breast cancer, stroke, acute myocardial infarction and prostate cancer.6

Pathophysiology of CLI and ischaemic pain

Most commonly, CLI is caused by atherosclerosis. Other causes include vasculitis, thromboembolic disease, arterial embolic disease, in situ thrombosis, cystic adventitial disease, thromboangiitis obliterans or trauma. Irrespective of the underlying cause, the pathophysiology of CLI is complex. There are three main mechanisms underlying the pathophysiology: haemodynamic abnormalities, oxidative stress and alterations in skeletal muscle metabolism. All compensatory mechanisms to retain skin perfusion become ineffective.

Chronic ischaemic pain has a significant neuropathic component. This is proposed to be secondary to a distal axonopathy affecting nerve fibres of all sizes. Blood flow in the lower limbs of patients with CLI correlates with neurological symptom scores and electrophysiological testing.7

Ischaemic pain and impact on quality of life

CLI is primarily characterised by pedal rest pain. It is typically worse at night (when the limb is no longer in a dependent position), often waking patients from their sleep. Pain from ulceration also occurs. Multiple studies have shown that chronic ischaemic pain negatively impacts on multiple dimensions of quality of life.8–10

Treatment of CLI

The therapeutic goals in treating CLI include increasing survival, relieving ischaemic pain, healing areas of ulceration, preventing major amputations, improving function and improving quality of life. TASC II recommends that for all patients with CLI, an early referral should be sent to a vascular specialist to plan for revascularisation.1 Simultaneously, a multidisciplinary approach to control pain, risk factors and comorbidities is recommended.1 Throughout the disease trajectory, pain control is important to improve quality of life, and to reduce the risk of phantom limb pain in patients who go on to require amputation.11

When open or endovascular intervention has failed, or is not possible, pharmacotherapy for CLI is the next step to consider. A 2010 Cochrane review concluded that there is no conclusive evidence for the long-term effectiveness and safety of prostanoids in patients with CLI, despite some positive results regarding rest-pain alleviation, healing of ulcers and amputations.12 With regard to vasoactive drugs, a Cochrane review found that intravenous naftidrofuryl for CLI was ineffective in reducing the symptoms of CLI.13

Palliation and CLI

TASC II reports that ultimately, the majority of care of patients with CLI is palliative in nature.1 In an ageing comorbid population, preferred revascularisation or surgery is often not an option. There are little data on the outcome of conservative therapy. Most research focuses on physician-reported outcome measures (graft patency, survival, and so on). Research studies including patient-reported outcome measures are limited. Recognising patients in need of palliative care, recording discussions about their management and a high standard of end of life care are all vital.14

Ideally, pain control is achieved by reperfusion of the ischaemic limb. When this is not possible or fails due to either the patient or disease status, pain management is challenging. Interventional pain procedures, such as spinal cord stimulation (SCS) and lumbar sympathectomy, may have a role in achieving pain control but evidence to date is inconclusive. Pain management is therefore challenging for multiple reasons: complex pathophysiology resulting in predominantly neuropathic pain, poor tolerance of strong opioids in a cohort with multiple comorbidities often including chronic kidney disease, regional anaesthesia inconsistently effective for ischaemic pain and a limited pool of research specifically targeting ischaemic pain.15

Patients with CLI have severe pain, poor quality of life and limited prognosis. If these patients are ultimately being treated in a palliative approach, what evidence do we have for the effectiveness of interventions to treat pain when all other options for limb salvage (revascularisation, surgery, pharmacotherapies) are exhausted? This systematic review was conducted to identify and evaluate the most effective therapies available to treat ischaemic pain in patients with CLI without options for limb salvage.

Objective

To identify and evaluate the effectiveness of pharmacological therapies to treat ischaemic pain secondary to non-reconstructable CLI.

Types of studies

All study designs were eligible for inclusion apart from single case reports. Single case reports were reviewed but excluded from the data extraction process. Studies that met the inclusion criteria were randomised controlled trials (RCTs), quasiexperimental studies, observational studies with/without control groups and case series.

Types of participants

Studies recruiting adult patients with CLI (as defined by TASC II1) were eligible for inclusion. Any underlying cause of CLI was included. Healthy volunteers with experimentally induced ischaemic pain were excluded.

Types of interventions

Any pharmacological interventions to treat ischaemic pain were included. Surgical and revascularisation procedures were excluded. All invasive interventions were excluded, such as SCS and lumbar sympathectomy. Detailed explanation of the roles of these interventions and reasons for exclusion are outlined below.

Types of outcome measures

The primary outcome measure was reduction in pain score, as measured by a visual analogue scale (VAS), Brief Pain Inventory20 or other scoring methods. Secondary outcome measures included opioid requirements, findings of allodynia, hyperpathia, or hyperalgesia on examination, hours of sleep, and depression and anxiety scores. Side effect profiles of each intervention were included in the data analysis. Only studies with the primary outcome measure related to ischaemic pain relief in CLI were included in the data analysis. This excluded studies with the primary outcome measures relating to limb salvage and secondary outcomes relating to pain management.

Search methods

Searching of three electronic databases was conducted (access via Ovid): MEDLINE (Ovid MEDLINE(R) In-Process and Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to December 2016), EMBASE (1974 to December 2016), Cochrane Library.

For each database, a detailed search strategy was developed (eg, online supplementary appendix 1).

Data collection and analysis

Lidocaine

Vahidi and colleagues compared intravenous lidocaine to intravenous morphine in patients with CLI.32 Prior to the infusion, the mean VAS score in the lidocaine group was 7.50 and in the morphine group was 7.65. After 15 min, the mean VAS score in the group that received lidocaine was lower than in the morphine group (5.75±1.77 vs 7.00±1.83; mean difference 1.25, 95% CI 0.095 to 2.405). At 30 min, the mean VAS score lowered further in the lidocaine group in comparison to the morphine group (4.25±1.48 vs 6.50±1.73; mean difference 2.25, 95% CI 1.218 to 3.282).

Ketamine

Mitchell and Fallon compared ketamine 0.6 mg/kg in 0.9% saline over 4 hours with normal saline over 4 hours on a background of the patient’s regular opioid usage.33 In the ketamine group, percentage pain relief attributed to medication improved from 50% preinfusion to 65% 24 hours postinfusion and 69% 5 days postinfusion. In the placebo group, percentage pain relief attributed to medication went from 58% preinfusion to 56% 24 hours postinfusion and 50% 5 days postinfusion (p<0.05 using the t-test and the Wilcoxon rank-sum test). The intervention group also showed an improvement in effect of pain on general activity (p<0.03) and on enjoyment of life (p<0.004). No statistically significant difference was seen in opioid requirements between the ketamine and placebo groups.

In the Persson et al ketamine trial, racemic ketamine hydrochloride was administered intravenously over 5 min at doses of 0.15, 0.3 and 0.45 mg/kg on respective study days.34 This was compared with morphine 10 mg intravenously over the same time interval. Ketamine 0.30 mg/kg provided total pain relief in seven of eight patients, whereas ketamine 0.45 mg/kg provided total pain relief in all eight patients. Pain relief lasted up to 10 min and then decreased steadily to a median value to 50% at 60 min. However, there was no statistically significant difference between the analgesic effect of ketamine 0.45 mg/kg and morphine 10 mg at peak effect times (5 and 20 min, respectively) (p<0.10, Wilcoxon test).

Gabapentin

In Morris-Stiff et al’s paper, the median pain score was 9 at presentation and significantly reduced compared with baseline each of the assessment days (day 4: 7 (p=0.001), day 7: 7 (p=0.0002), day 14: 6 (p=0.0004), day 28: 5 (p=0.0003)).35 Two of the 17 patients failed to show an improvement in pain scores. Fifteen patients reported an improvement in night pain, with secondary better sleep and perceived improvement in quality of life. The median dose was 1271 mg; four were adequately pain controlled on 300 mg three times a day, nine on 1200 mg, and the remainder on 600 mg three times a day. There was no control group to compare effect.

Transdermal buprenorphine + epidural morphine/ropivacaine

In Aurilio et al’s 2009 trial, there was a significant difference (p<0.0001) at the end point between the intervention group, with a mean VAS score of 10 mm (a reduction of 88%), and the control group, with a mean VAS score of 19 mm (a reduction of 77%).36 Patients receiving a 35 mg/hour buprenorphine patch demonstrated significantly lower Short-Form McGill Pain Questionnaire scores, mean total score and present pain intensity compared with those receiving the placebo patch (p<0.0001). At the end point, the mean score for sleep quality was significantly better in the intervention group (p<0.0001). The number of patients requiring rescue morphine was lower in intervention group during each week. There were no significant differences in the neurobehavioural status of the patients (p<0.165). In the 2005 trial, mean VAS at baseline was 85 in both groups.28 At day 15 it reduced to 20 in the intervention and 38 in the control, and at day 30 it reduced further to 10 in the intervention and 20 in the control. In the intervention, group mean hours of sleep improved from 3.5 to 5 to 8 and in the control from 3.5 to 4.5 to 6. No patients in the intervention group required additional morphine, in comparison to 11 in the control. No statistical analysis was performed on these results.

Adverse effects

All trials involved close monitoring for adverse effects. No side effects were reported in the intravenous lidocaine trial. In the lidocaine group, there were no reported adverse effects such as nausea, lightheadedness or perioral numbness. Following close monitoring, no serious complications (respiratory arrest, hypotension or cardiac arrhythmia) were observed. ECG readings were unchanged postinfusion. However, patients were only followed up for 30 min postinfusion. In Morris-Stiff et al’s trial, patients were followed for 28 days following commencement of gabapentin to monitor for side effects. There were no documented side effects. Both ketamine trials reported significant adverse effects in the intervention groups. In Mitchell and Fallon’s trial, despite all patients receiving oral haloperidol 1.5 mg on the evening of the infusion, 33% of patients reported feeling ‘more emotional than usual’ 24 hours after the ketamine; 6% of the placebo group reported this symptom (OR of 7.7; p=0.05). In Persson et al’s trial, side effects were divided into two groups: circulation and psychotropic. There was a marginal effect on systolic blood pressure after varying doses of ketamine (mean blood pressure rises approximately 10% for ketamine dose (0.45 mg/kg)). There was no significant effect on heart rate. All patients in the ketamine group experienced perceptual disturbances and psychotropic effects. These effects were dose dependent; at the highest dose all patients had side effects deemed ‘unacceptable’ even for a short-term treatment. Unacceptable side effects were effects which involved disturbances of perception, dizziness/vertigo or pronounced sedation. No patients received antipsychotic therapy to limit adverse effects. No patients withdrew because of adverse effects. Both Aurilio et al’s trials on the combination of buprenorphine and epidural morphine/ropivacaine found higher incidences of adverse effects in the control group (2009 trial: 59% vs 81%, p<0.001; 2005 trial: 45% vs 71%, no p value reported). All side effects reported were common opioid-induced effects (drowsiness, fatigue, constipation and nausea). Withdrawal from the trials occurred in one patient from the control group in the 2005 trial and two patients from the control group in the 2009 trial. The higher rate of symptoms reported in the control group was felt to be secondary to the increased need for additional rescue doses of epidural morphine in the control group.