Systematic review of pharmacological therapies for the management of ischaemic pain in patients with non-reconstructable critical limb ischaemia

Abstract

BackgroundCritical limb ischaemia (CLI) is a severe manifestation of peripheral arterial disease, characterised by chronic ischaemic rest pain, ulcers or gangrene. Management of ischaemic pain is challenging in patients with no options for revascularisation and optimal pharmacological therapies have not been established.ObjectivesTo identify and evaluate the effectiveness of pharmacological therapies to treat ischaemic pain secondary to non-reconstructable CLI.MethodsThis systematic review was reported in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. Comprehensive searches of three electronic databases, a PubMed-related articles link search, grey literature search and hand-searches of the bibliographies of relevant papers and textbooks were performed. Studies recruiting adult patients with CLI of any aetiology were eligible for inclusion. Surgical and revascularisation procedures, and all invasive interventions were excluded.ResultsOf 792 studies, six met full inclusion criteria. These studies researched the use of intravenous lidocaine, intravenous ketamine, oral gabapentin and the combination of transdermal buprenorphine and epidural morphine/ropivacaine infusion. All studies showed an improvement in severity of ischaemic pain in CLI but with varying side effect profiles and quality. The extracted studies showed substantial heterogeneity and therefore a meta-analysis was not performed.ConclusionThe pharmacological management of pain secondary to non-reconstructable CLI is a challenging review topic. No recommendations of pharmacological agents can be made following this review but a number of novel approaches to manage pain in this cohort have shown positive results and require further investigation.

Perioperative patient-controlled regional analgesia versus patient-controlled intravenous analgesia for patients with critical limb ischaemia: a study protocol for a randomised controlled trial

“…We also hope this study offers a reference for the non-surgical patients. Although revascularisation has been the most effective treatment for patients with CLI, some patients’ arteries are impossible to revascularise and require other treatments such as drugs, 26 transcutaneous electrical stimulation, 27 peripheral blood mononuclear cells therapy 28 or lumbar sympathectomy 29 to relieve pain and/or increase peripheral perfusion to avoid amputation. For those patients with non-reconstructable arteries, long-term PCRA may be less invasive and adequate for both analgesia and perfusion.…”

Partnering with Palliative Care: A Case Report of Severe Pain in Critical Limb Ischemia Treated Successfully with a Continuous Popliteal Nerve Catheter

“…However, many patients with CLI are ultimately referred to palliative care for pain management services as they may be approaching end of life due to nonreconstructable CLI, such as in our case report. In fact, the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) states that the management of CLI is usually palliative [25]. Moreover, patients may be unfit for surgery, while others may have persistent distal ischemia with pain even in the presence of a functioning revascularization [26].…”

Pain Management in People with Diabetes-Related Chronic Limb-Threatening Ischemia

“…However, the clinical characteristic of chronic ischemic pain in LEAD is diverse, ranging from asymptomatic to intermittent claudication, rest pain, nonhealing ulcers, and eventually gangrene. Both the pathophysiology and mechanism of ischemic pain remain unclear, but several mechanisms have been proposed: hemodynamic abnormalities, oxidative stress, and alterations in skeletal muscle metabolism [ 32 ]. Besides, the reduction in arterial perfusion in the affected limb leads to the accumulation of metabolites; increased acidity in the ischemic tissue and the onset of central sensitization are present in patients with CLTI [ 17 ].…”

“…Although revascularization strategy has been emphasized in the treatment of CLTI, the adequacy of pain management is entirely based on the drug of choice. A recent systematic review reported pharmacological therapies for the management of ischemic pain in patients with nonsalvageable CLTI [ 32 ]. Six studies were identified from 792 studies that met full inclusion criteria, and evaluated the use of intravenous lidocaine [ 36 ], oral gabapentin [ 37 ], intravenous ketamine [ 38 , 39 ], and the combination of transdermal buprenorphine and epidural morphine/ropivacaine infusion [ 40 , 41 ].…”

“…They found that all studies had shown an improvement in severity of ischemia pain in CLTI but with varying side effects. Therefore, no pharmacological agents can be recommended in this case because of the complex pathophysiology of pain in CLTI and limited clinical evidence [ 32 ]. Importantly, clinicians and patients should be aware of the consequences of pain syndrome in diabetes and the profound progression that can occur in the face of an ischemic limb with concomitant neuropathy masking symptoms.…”