Symptoms and General Pathology

All Conditions

Nervous System Diseases

Behaviors and Mental Disorders

Neoplasms

Pain

Phantom Limb

Neuroma

Neuralgia

Perceptual Disorders

Neurobehavioral Manifestations

Neurologic Manifestations

Pain, Postoperative

Postoperative Complications

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Peripheral Nervous System Diseases

Neuromuscular Diseases

The surgical procedure comprises three steps: preparation of the donor nerve, identification of a motor branch to the targeted muscle, and nerve coaptation. To prepare the donor nerve, the surgeon will identify the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Next, the surgeon will identify a motor branch to a nearby target muscle and will confirm muscle contraction using a hand-held nerve stimulator. The motor branch to the target muscle will be transected as close as possible to its entry point without tension. In the final step, the previous nerve stump from which the neuroma was resected will be transferred and coapted to the newly severed motor branch that innervates the target muscle and secured by 2-3 non-resorbable monofilament sutures. The surgery time is approximately 2-3 hours and it takes place in the hospital.

The RPNI procedure involves construction of a residual peripheral nerve split into several nerve fascicles and implanted into free skeletal muscle grafts. First, the surgeon identifies the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Then, a longitudinal intraneural dissection will be performed exposing its fascicles. Next, autologous muscle grafts will be harvested from a healthy donor site, and the dissected nerve stumps will be placed parallel to the muscle fibers. The nerve stump will be secured to the muscle graft, thereafter the graft will be wrapped around the nerve stump and anchored in the folded graft, thus creating an RPNI. This will be repeated for each fascicle obtained from splitting the transected nerve. Lastly, the RPNIs will be placed in a protected area. The surgery time is approximately 2-3 hours and it takes place in the hospital.

The standard neuroma treatment, also called neuroma transposition, includes excision of the terminal neuroma and burying the nerve into an adjacent deep muscle.The standard neuroma treatment entails the excision of the terminal neuroma and then implanting the nerve into an adjacent muscle. Firstly, the surgeon will identify the nerve with a painful neuroma and thereafter resect the neuroma up to healthy fascicles. Next, the surgeon will identify a nearby muscle which is not involved in joint motion and has limited output opportunities for the nerve. The nerve will then be channeled at least 1 cm inside the muscle without applying any tension to it and secured by 1-2 non-resorbable monofilament sutures. The identified nerve with the painful neuroma will not be treated with any additional therapy than the resection (e.g., diathermy, pharmacotherapy, crushing, etc.). The surgery time is approximately 1-2 hours and it takes place in the hospital.

Surgical procedure used to rewire injured proximal nerves to motor nerves directly innervating an otherwise redundant target muscle.

Targeted Muscle Reinnervation (TMR)

Surgical procedure where the the nerve is split into fascicles and wrapped in free muscle grafts.

Regenerative Peripheral Nerve Interface (RPNI)

Surgical procedure where the neuroma is excised and the nerve stump is buried in an adjacent deep muscle.

Standard neuroma treatment, neuroma excision, and muscle burying

Emily Pettersen, MSc

Max Ortiz Catalan, PhD

Jason Ko, MD, PhD

Gregory Dumanian, MD, PhD

Ian Valerio, MD, PhD

Kyle Eberlin, MD, PhD

Paul Cederna, MD, PhD

Theodore Alexander Kung, MD, PhD

Michael Lo, MD, PhD

Michael Leung, MD, PhD

Adil Ladak, MD, PhD

Hollie Power, MD, PhD

Jacqueline Hebert, MD, PhD

Juan Manuel Breyer, MD, PhD

Paolo Sassu, MD, PhD

Francesca Pedrini, MD

Carina Reinholdt, MD, PhD

Hannes Granberg, MD

Aidan Roche, MD, PhD

Andrew Hart, MD, PhD

Lorraine Harrington, MD, PhD

This is a double-blind randomised controlled trial (RCT) which compares the effectiveness of three surgical techniques for alleviating residual limb pain (RLP), neuroma pain and phantom limb pain (PLP). The three surgical treatments are Targeted Muscles Reinnervation (TMR), Regenerative Peripheral Nerve Interface (RPNI), and an active control (neuroma excision and muscle burying). Patients will be follow-up for 4 years.

Residual limb pain (RLP), neuroma pain, and phantom limb pain (PLP) can develop after the loss of a body part and fall within the umbrella term postamputation pain. However, the underlaying causes to postamputation pain are diverse and must be addressed accordingly. Surgical treatments for RLP have become a popular approach and have shown great potential for successful outcomes. The two surgical interventions, Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI), are globally used in pain management therapies.

This is a multi-centre, double-blind, superiority RCT which takes place at 9 hospitals in 7 countries:the Sahlgrenska University Hospital in Gothenburg, Sweden; the Rizzoli Orthopaedic Institute in Bologna, Italy; the University of Alberta Hospital in Edmonton, Canada; Worker Hospital in Santiago, Chile; the NHS Lothian, NHS Clyde \& Greater Glasgow, and NHS Grampian, UK; Dandenong Hospital, Monash Health in Melbourne, Australia; the Northwestern Memorial Hospital in Chicago, USA; the University of Michigan Health System in Ann Arbor, Michigan, USA; and within the Massachusetts General Hospital in Boston, USA. One hundred ten participants will be recruited and randomly assigned to one of three surgical treatments (TMR, RPNI, or control) in an equal allocation ratio (n = 37 per group). Each participant will be followed up short term (1, 3, 6, and 12 months post-surgery) and long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participants are unsatisfied with the outcome of the treatment, they may request one of the other treatments. In such a case, a medical evaluation and further treatment options will be discussed in consultation with the clinical investigator at the site.

The study design is chosen to be able to follow RLP, neuroma pain and PLP intensity before and after surgical treatment as well as to investigate how pain develops up to four years post-surgery. The evaluation methods in the study are based on previously used methods in the literature for RLP-, neuroma- and PLP-related pain research. The questionnaires are previously used in clinical settings.

Surgical Treatments for Postamputation Pain

Difference in residual limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.

Difference in neuroma pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.

Difference in phantom limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-months follow-up visit.

Vastra Gotaland Region

Göteborg University

Chalmers University of Technology

Istituto Ortopedico Rizzoli

Hospital del Trabajador de Santiago

NHS Lothian

NHS Greater Clyde and Glasgow

NHS Grampian

Northwestern Memorial Hospital

University of Michigan

Massachusetts General Hospital

Dandenong Hospital

The Bionics Institute of Australia

University of Alberta

Center for Bionics and Pain Research

Professor

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. These nerves are then "cleaned up" to be rerouted and connected to smaller nerves that control individual muscles. The connection to nerves that run into muscles is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 2 - 4 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. The nerves are then "cleaned up" to enhance the possibility of healthy healing. Then the surgeon takes a small sample from a muscle (usually one close by to the nerves that are being operated on but sometimes through a second incision in the arm or leg, depending on the exact medical situation) and form something called a "muscle graft". The muscle graft is used to wrap the cleaned ends of the nerves mentioned above. This is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 1 - 3 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. The nerves are then "cleaned up" to enhance the possibility of healthy healing. The surgeon will then identify a local muscle along with a small artery and vein that supply blood to part of the muscle. A small sample of muscle, still attached to the artery and vein, is then created. The nearby nerves are then nestled into this segment of muscle that is still connected to the artery and vein. This is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 2 - 4 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

Surgical procedure to connect injured proximal nerve stumps to motor nerve branches directly innervating a muscle

Surgical procedure to wrap the ends of injured nerves in small muscle grafts

RPNI

Surgical procedure that creates a small muscle graft that is both denervated and vascularized, which will then receive the damaged nerve ending

VDMT

Sami Tuffaha, MD

Amputees often suffer from relentless pain and disability resulting from symptomatic neuromas within the amputation stumps. When conservative measures fail to address these symptoms, two contemporary surgical approaches to treat symptomatic neuromas have become the most popular. Targeted muscle reinnervation (TMR) is a procedure which involves transferring the injured proximal nerve stump into a terminal nerve branch entering muscle, such that the axons from the proximal nerve stump will regenerate into the muscle and thereby prevent neuroma recurrence. Regenerative peripheral nerve interfaces (RPNIs) are muscle grafts placed on the proximal nerve stumps that serve as targets for the regenerating axons from the proximal nerve stumps.

While TMR and RPNIs have demonstrated promise for the treatment of symptomatic neuromas, prospective comparative data comparing outcomes with these two approaches is lacking.

The investigators have recently developed a novel approach to treat symptomatic neuromas that provides vascularized, denervated muscle targets (VDMTs) for the axons regenerating from the severed proximal nerve stump to reinnervate. This is accomplished by islandizing a segment of muscle on its blood supply and ensuring complete denervation prior to implanting the neighboring transected nerve stump into this muscle. VDMTs offer theoretical benefits in comparison to RPNIs and TMR that the investigators also aim to test in the proposed study.

The investigators' objective is to enroll amputees with symptomatic neuromas into a prospective study in which amputees will be randomized to undergo TMR, RPNI, or VDMT and subsequently monitored for pain and disability for 1-year post-operatively. The investigators' specific aims are as follows: 1) Test the hypothesis that VDMTs are more effective than TMR and RPNIs with regards to treating pain and disability associated with symptomatic neuromas; 2) Provide the first level one, prospective data directly comparing the efficacy of TMR and RPNIs.

Extremity amputations are common operations both in the United States and other areas of the world. It is estimated that there are nearly 2 million adults living in the United States alone. Etiologies for extremity amputation are diverse but the most common indications include complications of type 2 diabetes, non-diabetic peripheral vascular disease, trauma, and oncologic conditions. Given the increasing prevalence of several of these pathologies, conservative estimates suggest that the population of people living with an amputated limb will likely double within the next several decades.

Patients who undergo limb amputation are at significant risk of developing chronic neuropathic pain as a result of symptomatic neuroma formation, due in large part to the abundance of sizeable nerves within the extremities that are necessarily transected as part of the procedure. There are two distinct forms of pain experienced by patients who have undergone major extremity amputations. Residual limb pain is the more straightforward form of post-amputation pain attributable to neuroma formation within the amputation stump. Following peripheral nerve transection, axons regenerating from the proximal stump tend to form aggregates of disorganized neural growth called neuromas. Some neuromas will produce severe, intractable pain causing significant impairment in prosthetic fit and function, activities of daily living, and quality of life. Some estimates place the prevalence of residual limb pain attributable to neuroma formation as high as 75%. The other form of pain is known as phantom limb pain. While the underpinnings of phantom limb pain are the subject of ongoing debate, it is thought by many to arise from chronic stimulation of the cerebral cortex with painful inputs from peripheral neuromas, leading to unpredictable and poorly characterized reorganization of the cortex. Informed estimates of phantom limb pain prevalence as high as 85% have been reported. Successful prevention and treatment of symptomatic neuromas in the setting of limb amputation is therefore of paramount importance given the central role in the pathogenesis of chronic post-amputation limb pain encompassing both residual limb pain and phantom limb pain.

Treatment options for chronic post amputation pain caused by symptomatic neuromas are diverse. Medical options for both phantom limb pain and residual limb pain have been met with limited success. Despite the widespread use, the utility of neuromodulating medications, such as gabapentin, has been called into question by recent large scale meta-analyses that failed to demonstrate meaningful improvements. Neurotoxins, such as botulinum toxin, have also been studied and found to offer limited, if any, pain resolution.

One of the most commonly used surgical approaches to treat and prevent symptomatic neuromas involves burying the proximal nerve stump into nearby muscle. There is a widely-held misconception that burying a proximal nerve stump into muscle will prevent a neuroma from forming. However, elegant animal studies have proven that regeneration of a neuroma is virtually guaranteed because innervated muscle will not accept additional innervation from regenerating neurons.

In the past decade, two other surgical treatments for chronic post-amputation limb pain have come into vogue. Targeted muscle reinnervation (TMR) was initially pioneered as a means of providing intuitive control of advanced prostheses and only later observed to reduce neuroma pain. TMR involves transferring the proximal nerve stump of the injured nerve into a nearby distal motor branch. Early results are promising. A recently published randomized, controlled trial demonstrated the superiority of the TMR approach over the 'bury in muscle' approach, so much so that the trial concluded prematurely due to the superiority of the TMR compared to the historical technique.

The other recently developed and widely popularized option for surgical treatment of chronic post-amputation limb pain involves creation of a regenerative peripheral nerve interface (RPNI). Similar to TMR, the RPNI was initially conceived as a method to provide an interface with an advanced neuroprosthetic prior to being employed as a treatment strategy for neuromas. RPNIs are muscle grafts that are coapted to the ends of severed proximal nerve stumps. This technique has gained popularity because of its technical simplicity and promising early clinical data. In contrast to the 'bury in muscle' approach, RPNIs are denervated at the time of harvest and have been shown to accept reinnervation via direct neurotization from the proximal nerve stump.

To address possible limitations of the strategies described above, the investigators propose using muscle targets similar to RPNIs but maintaining vascularity - a vascularized, denervated muscle target (VDMT). This is accomplished by raising a portion of muscle on a vascular leash in proximity to the transected nerve. Perforating branches from larger blood vessels that perfuse adjacent muscle can be found in abundance throughout the extremities. Any nerves traveling with the vascular leashes will be divided to ensure complete denervation of the muscle. Therefore, VDMTs will be receptive to reinnervation from the implanted proximal nerve stump, maintain vascularity such that the VDMTs can be large enough to supply an abundance of sensory receptors (spindle cells, Golgi apparati, etc) to accept regenerating axons, and avoid the use of a nerve coaptation. In short, the VDMT offers possible enhancements to the surgical techniques currently in use.

In terms of surgical outcomes, there is a robust body of data surrounding the TMR and RPNI operations, with some more recent reports providing pre- and post-operative pain scores for the individual operations. With the exception of one study that prospectively compared TMR to the historical gold standard of neuroma excision and implantation into surrounding tissue, there is a startling lack of prospective data on pain outcomes. Furthermore, the investigators are not aware of prospective, head-to-head comparative data for RPNI vs TMR. Robust, prospective, comparative data is now needed to validate the VDMT approach and assess its efficacy in comparison to the other established techniques.

It is of prime importance to surgeons who perform extremity amputations (eg orthopedic surgeons, vascular surgeons, trauma surgeons, plastic surgeons, and podiatrists) as well as those who perform salvage procedures for post-amputation extremity pain to understand the potential of these operations in treating this pain. Physicians are still lacking evidence-based treatment guidelines. With the generation of this data, surgeons and patients can make more informed decisions about which operative intervention provides the highest likelihood of durable, significant pain relief.

Surgical Treatments for Neuroma Pain in Amputees

A Randomized Trial Comparing Surgical Treatments for Neuroma Pain in Amputees

Pain score will be assessed using the numerical pain score (0-10) with 0 representing no pain and 10 representing the worst pain.

The Plastic Surgery Foundation

Johns Hopkins University

Headache

Head and Neck Neoplasms

Analgesics

All Drugs and Chemicals

Central Nervous System Depressants

Anticonvulsants

Psychotropic Drugs

Analgesics, Opioid

Gabapentin

Anti-Anxiety Agents

Excitatory Amino Acid Antagonists

Neurotransmitter Agents

Patients randomised to the experimental group will receive a prescription for a gabapentin starting dose of 100 mg three times a day (ter in die, t.i.d) /day per orally, additional to the analgesics according to standard local practices.

Gabapentin dosage may be gradually increased based on individual patient response and tolerability, and as per standard practice in accordance with the drug label. The dose can be further increased in 300 mg/day increments (dose increments of 50% - 100%) every two to three days, up to a maximum dose of 3600 mg/day. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of two weeks, and to reach 3600 mg/day is a total of three weeks.

Patients randomised to the control group will receive a prescription for a matching placebo. The starting dose will be the same as in the experimental group (100 mg three times a day per orally), additional to the analgesics according to standard local practices. Placebo can optionally follow the same dose scheme as described in the experimental arm.

Gabapentin will be administrated orally, with or without food, and should be swallowed with sufficient fluid intake (e.g. a glass of water). Since head and neck cancer patients frequently experience swallowing difficulties, gabapentin capsules will be provided to enable opening of the capsule and use of the contents for mixture with food or liquids. Moreover, gabapentin powder can be dissolved in water to enable injection of the drug into a percutaneous endoscopic gastrostomy tube.

Placebo will be administrated orally, with or without food, and should be swallowed with sufficient fluid intake (e.g. a glass of water). Since head and neck cancer patients frequently experience swallowing difficulties, placebo capsules will be provided to enable opening of the capsule and use of the contents for mixture with food or liquids. Moreover, placebo powder can be dissolved in water to enable injection of the drug into a percutaneous endoscopic gastrostomy tube.

Placebo

Tom Boterberg, MD, PhD

A multi-centre, double-blind, randomized-controlled trial to study the efficacy and safety of gabapentin to reduce the need for strong opioid use in the treatment of radiation-induced pain in head and neck cancer (HNCA) patients undergoing a curative 7-week radio(chemo)therapy course with curative intent. The aim of this study is to establish if addition of gabapentin is more effective in reducing the need to start (or dosage-increase) a strong opioid for HNCA pain than a matching placebo additional to standard pain management (WHO-ladder step 2 and 3).

Although pain is a major symptom in head and neck cancer (HNCA) patients, few studies focus on pain management in this population. Current optimal HNCA pain control usually requires the use of a strong opioid (WHO-ladder step 3), increasing the risk of opioid side effects and toxicities. Gabapentin, originally an anticonvulsant drug, has been effectively used off-label to treat multiple neuropathic pain syndromes such as cancer pain, and has been suggested to reduce the need for high doses of strong opioids in HNCA patients under radio(chemo)therapy. A multi-centre, phase III, double-blind, randomised-controlled trial will be set up randomising patients between the experimental group (E) receiving gabapentin, or the control group (C) receiving a matching placebo, both in addition to standard analgesic therapy (steps 2 and 3 on WHO-ladder). The investigators aim to establish if addition of gabapentin is more effective in reducing the need to start (or dosage-increase) a strong opioid for HNCA pain than a matching placebo additional to standard pain management (WHO-ladder step 2 and 3), in HNCA patients scheduled for a curative 7-week radio(chemo)therapy course.

Randomised-controlled trial where patients are randomised to either the experimental group (E) receiving gabapentin or the control group (C) receiving a matching placebo, both in addition to standard analgesic therapy (WHO ladder steps 2 and 3).

Both patient groups will receive gabapentin or a matching placebo additional to the standard analgesic therapy, and will be asked to consume the content following the predefined directions provided to them. Both the investigators and the patients will be blinded for the IMP, since gabapentin and the matching placebo will appear identical.

The clinical pharmacist responsible for clinical trials as well as Bimetra clinics will receive a sealed envelope from the statistician with the information necessary for decoding.

Study of Efficacy and Safety of Gabapentin to Reduce the Need for Strong Opioid Use in Head and Neck Cancer Patients.

Multi-centre, Double-blind, Randomized-controlled Trial to Study the Efficacy and Safety of Gabapentin to Reduce Strong Opioid Use in Treatment of Radiation-induced Pain in Head and Neck Cancer Patients During Curative Radio(Chemo)Therapy.

Through pain diary, weekly visit by doctor and research assistant, the need for (dose-escalation of) strong opioid will be assessed.

Through pain diary, weekly visit by doctor and research assistant, patients will be asked to rate their pain

Pain assessment of subtypes of patients, according to their tumour location, through the 0-10 numeric visual analogue pain rating scale. This scale is a tool to measure the pain of patients, with a score of 0 if the patient has no pain, a score of 5 if the patient has moderate pain and a score of 10 if the patient copes with the worst possible pain. So higher values represent worse pain.

Pain assessment of subtypes of patients, according to their tumour location, through the Neuropathic Pain Scale. Patients give a score between 0 until 10 on different aspects of pain as pain sharpness, heat/cold, dullness, intensity, unpleasantness, and surface vs. deep pain which all represent the subtypes of the Neuropathic Pain Scale. A score between 0 and 10 will be assigned to these different subtypes of pain, with a score of 0 if the patient has no pain, a score of 5 if the patient has moderate pain and a score of 10 if the patient copes with the worst possible pain. So higher values represent worse pain. The scores on all these subscales are not combined as we are interested in the subtypes of pain themselves.

Pain assessment of subtypes of patients, according to their tumour location, through the Brief Pain Inventory (Short Form).

Treatment-related toxicities will be scored by the local physician

Effect on hospitalisation will be assessed by the local physician and the research assistant

Effect on the placement of percutaneous endoscopic gastrostomy tube will be assessed by the local physician and research assistant

Monitoring of opioid therapy until primary endpoint

Monitoring of drug tolerance by local physician on weekly visits. The effects of the drug can either be unchanged, lessened, or increased. According to this, the physician will adapt the dose for patient. This will be weekly reported by the local physician to the research associate.

Monitoring of drug safety by local physician according to treatment-related toxicities, scored weekly by the local physicians according to the Common Terminology Criteria of Adverse Events (NCI CTCAE 5.0). Analgesic-induced side effects will be evaluated with regard to nausea, constipation, sleepiness, dizziness, confusion, hypersensitivities, urinary retention, pruritus and respiratory depression.

Weekly monitoring of drug compliance by local physician and research associate. Research associate counts amount of medication (gelules) that are left to assure there is therapy compliance.

Through pain diary, weekly visit by research assistant, patients will be asked about the ease of use of trial medication

Continuous follow-up of patients (weekly or daily) by research assistant

Through weekly visit by research assistant, patients will be asked how satisfied they are with current trial medication

Patients will be able to agree or disagree with the collection of blood samples on the informed consent form as these translational aspects are not an obligatory part of this trial. In patients who give their consent, one SST blood sample and one EDTA blood sample will be collected at the time of inclusion.

General Hospital Groeninge

KU Leuven Campus Kulak Kortrijk

Anglia Ruskin University

University Hospital, Ghent

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Lung Neoplasms

Syndrome

Chronic Pain

Chronic Graft Versus Host Disease

Pharmaceutical Solutions

Botulinum Toxins

Botulinum Toxins, Type A

abobotulinumtoxinA

Onabotulinum toxin A is reconstructed with 4 ml of normal saline in a vial containing 100 U (Allergen Units).

At a single treatment session, test subjects receive a series of subcutaneous injections with 2,5 U Onabotulinum toxin A equivalent to 0,1 ml of solution after reconstruction. One injection is given per 1 square centimeter in the painful area in relation to the scar on the chest wall. The maximum number of subcutaneous injections is 40, equivalent to a maximum dose of 100 U of Onabotulinum toxin in a total volume of 4 ml solution. The subcutaneous injections are administered using 26G 0.45 x 15 mm cannulae and 1 ml syringes.

At a single treatment session, test subjects receive a series of subcutaneous injections with one injection per 1 square centimeter in the painful area in relation to the scar on the chest wall with an inert solution, i.e. 0.1 ml injections of normal saline up to a total volume of 4 ml, depending on the area of the painful area. The subcutaneous injections are administered using 26G 0.45 x 15 mm cannulae and 1 ml syringes.

Onabotulinum Toxin A

Normal saline

Allan V Danielsen, MD

Jan J Andreasen, MD PhD

Chronic postsurgical pain following lung cancer surgery is common with and 20-60 % develop chronic pain which persists more than six months after surgery. Causes and health impact of this pain have been comprehensively studied. Current treatment consists of combination of pain medication, physiotherapy and psychological therapy.

Botulinum Toxin A (BTX-A) has shown promising effects in a variety of chronic postsurgical pain syndromes. The use of BTX-A in lung cancer patients has only been presented in few case reports. No randomized controlled trials (RCT) have been executed to date.

Study objectives:

Determine recruitment potential among cured lung cancer patients with chronic postsurgical pain for an RCT and if the method of BTX-A administration is feasible and acceptable. Further more, this study will contribute to the stage testing of the hypothesis that chronic pain following thoracic surgery can be treated with BTX-A.

Methods:

Recruitment of test subjects:

Participiants are recruited among former lung cancer patients with chronic postsurgical pain, who have undergone radical treatment for lung cancer at the Department of Cardiothoracic Surgery, Aalborg University Hospital. Potential test subjects are invited by mail / e-mail.

Randomization and blinding:

Participants are randomized to receive a single series of subcutaneous injections with either Onabotulinum Toxin A (active agent) or inactive normal saline (Placebo) at the former operation site. Neither participant nor investigator will know which treatment is given until the end of the trial.

Data collection:

Data is collected by questionnaires delivered and answered by mail or digitally.

Data on the possible effects and possible adverse reactions are collected at multiple times until three months after treatment.

Chronic postsurgical pain (CPP) following lung cancer surgery is common with an observed prevalence of 20-60 %. Causes and health impact have been comprehensively studied. Current treatment consists of combination of pain medication, physiotherapy and psychological therapy.

Botulinum Toxin A (BTX-A) has shown promising effects in a variety of chronic postsurgical pain syndromes. The use of BTX-A in lung cancer patients has only been presented in few case reports. No randomized clinical controlled trials (RCT) has been executed to date.

Study objectives:

Primary:

Determine recruitment potential among cured lung cancer patients with CPP for an RCT and if the method of BTX-A administration is feasible and acceptable to the test subjects.

Secondary:

Early stage testing of the hypothesis that CPP following thoracic surgery can be treated with this novel method.

Methods:

Recruitment of test subjects:

Test subjects are recruited among former lung cancer patients with chronic postsurgical pain, who have undergone radical treatment for lung cancer at the Department of Cardiothoracic Surgery, Aalborg University Hospital. Potential test subjects are invited by mail / e-mail.

Randomization and blinding:

Test subjects are randomized to receive a series of injections with either Onabotulinum Toxin A (active agent) or inactive normal saline (Placebo). Neither test subject nor investigator will know which treatment is given until the end of the trial.

Experimental treatment:

The investigator examines the skin area of the test subject at the operation site and performs a sensory examination with pin prick and sensory brush. The area is located and marked and divided into quadrants of one square centimeter. An area of maximum 40 square centimeters is marked.

At a single treatment session, test subjects receives either active agent or placebo through a series of subcutaneous injections. One injection is given in each marked quadrant of the treatment area. The maximal number of injections is 40.

Follow-up:

After the treatment, test subjects report pain symptoms and intensity, use of pain medication and occurrence of adverse events weekly.

After 30 and 90 days after treatment more comprehensive and additional data is collected concerning neuropathic symptoms, activities of daily life, general health and level of function.

Data collection Data is collected by questionnaires delivered to test subjects by mail or digitally.

Endpoints:

Primary:

1. Recruitment of 30 test subjects.
2. Half of the first half of included test subject must complete the treatment.
3. Half of test subjects in total mus complete the treatment.

Secondary:

1. Pain at rest, coughing and when active Numerical rating score (NRS) for presence of pain before and after treatment and course of pain symptoms.
2. General Health Short form 36 Health Survey on physical, social and mental level of function on a score from 0 to 100.
3. Neuropathic Pain Symptoms Inventory (NPSI) NRS
4. Activities of daily life Impact and intensity of pain categorically in 16 situations of daily life.
5. Patient's Global Impression of Change (PGIC) Rating of global change perceived by the test subject from "More Worse" to "Much better" and a scale from 0 to 10.

Botulinum Toxin A as Treatment for Chronic Postsurgical Pain Following Lung Cancer Surgery

Botulinum Toxin A as Treatment for Chronic Postsurgical Pain Following Lung Cancer Surgery: a Randomized Controlled Pilot Trial

Half of the first half of included test subject must complete the treatment.

Recruitment of 30 test subjects within twelve months.

Proportion of test subjects terminating the treatment procedure after randomization by request due to unacceptable pain or discomfort during the procedure.

Numeric Rating Scale, range 0 (no pain) to 10 (worst pain imaginable) in whole numbers

Impact and intensity of pain categorically in 16 situations of daily life. Categorically reported as "Avoid", "Major restriction", "Some restriction", "Minor restriction", "No restriction" or "Do not perform"

Rating of global change perceived by the test subject from "More Worse" to "Much better" and a scale from 0 to 10.

Short form 36 Health Survey on physical, social and mental level of function on a score from 0 to 100.

Evaluation of pain/discomfort at administration of BTX-A using subcutaneous injection in the skin of the chest wall. Numeric Rating Scale, range 0 (no pain) to 10 (worst pain imaginable) in whole numbers

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Surgical Treatments for Postamputation Pain	NCT05009394	Residual Limb P... Amputation Neur... Phantom Limb Pa... Pain, Neuropath... Pain, Nerve	Targeted Muscle... Regenerative Pe... Standard neurom...	18 Years -	Center for Bionics and Pain Research
Surgical Treatments for Neuroma Pain in Amputees	NCT04204668	Pain, Neuropath... Amputation Neur... Phantom Limb Pa...	TMR RPNI VDMT	18 Years -	Johns Hopkins University
Study of Efficacy and Safety of Gabapentin to Reduce the Need for Strong Opioid Use in Head and Neck Cancer Patients.	NCT03747562	Head Neck Cance... Radiation Neuro... Pain, Neuropath...	Gabapentin Placebo	18 Years -	University Hospital, Ghent
Botulinum Toxin A as Treatment for Chronic Postsurgical Pain Following Lung Cancer Surgery	NCT04585620	Chronic Pain Post-thoracotom... Pain, Neuropath... Pain, Postopera...	Onabotulinum To... Normal saline	18 Years -	Aalborg University Hospital
Cancer in Patients With Gabapentin (GPRD)	NCT01236053	Pain, Neuropath... Epilepsy Renal Pelvis Ca... Pancreatic Canc... Breast Cancer Nervous System ... Chronic Pancrea... Stomach Cancer Renal Cell Carc... Diabetes Bladder Cancer Bone and Joint ... Penis Cancer Anal Cancer Cancer Renal Cancer	Gabapentin pres...	-	GlaxoSmithKline
Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)	NCT03723447	Pain, Postopera... Crohn Disease Inflammatory Bo... Colorectal Canc... Gastrointestina... Gastrointestina... Digestive Syste... Pain Pain, Neuropath... Intestinal Dise...	Liposomal bupiv... Bupivacaine/epi...	18 Years - 90 Years	Cedars-Sinai Medical Center

Spots Global Cancer Trial Database for pain, neuropathic