Use of Analgesic Treatment to Reduce Signs of Pain in Patients With Disorders of Consciousness.

Use of Analgesic Treatment to Reduce Signs of Pain in Patients With Disorders of Consciousness: a Double-blind Placebo-controlled Clinical Study.

The purpose of this study is to characterize and improve pain and nociception management in patients with disorders of consciousness (DOC). This project is divided into two phases, a first phase to evaluate pain level and a second phase which consist of a clinical trial to evalute pain medication efficacy.

The main aim is to evaluate the use of the Nociception Coma Scale-Revised (NCS-R) and its cut-off score (i.e., 5) as an assessment and management tool to define guidelines for managing pain in patients with DOC. In this double-blind, placebo-controlled clinical study, we will evaluate the use of analgesic treatments in reducing pain in subacute/chronic patients. The project will also allow us to validate the NCS-R cut-off score defined previously.

Study Overview

• Status: Completed
• Conditions: Disorders of Consciousness; Minimally Conscious State; Severe Brain Injury; Post-comatose Non-communicative Patients; Vegetative State
• Intervention / Treatment: Drug: Analgesic administration; Drug: Placebo administration

Detailed Description

The study will be performed within one week (i.e, 7 days) and consists of two phases:

• Phase 1 "Patients selection (D0)": Patients will be assessed by the NCS-R during experimental stimulation (rest, tactile, noxious) and mobilizations (physiotherapy). Patients with potential pain will be included in the phase 2.
• Phase 2 "Analgesic administration (D1 and D2)": double-blind placebo-controlled randomized clinical trial on potential responders identified in phase 1. A medical doctor of our team will suggest to the physician in charge to prescribe the dedicated medication. One placebo and one real treatment will be administered on day 1 and 2 by the nurses at least half-hour before the physiotherapy. Randomization between day 1 and 2 will be applied at that time.

For each day of phase 1 and 2, several assessments will be performed: NCS-R, CRS-R and spasticity assessment.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Liège, Belgium, 4000
    • Centre hospitalier universitaire de Liege

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 95 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have had an acquired brain injury with a loss of consciousness > 28 days (patients) or have no history of previous brain injury (healthy controls)
• Legally authorized surrogate available to provide informed consent.
• Diagnosis of vegetative/unresponsive (VS/UWS) or minimally conscious state (MCS) or emergence of the minimally conscious state without communication (eMCS; as defined by the CRS-R, see above).
• Medically stable (i.e., no systemic illness or disease).
• Patients with NCS-R score during mobilization above or equal to the previously determined cut-off score or NCS-R scores during mobilization equivalent to NCS-R score obtain during nociceptive stimulation will be included in the second phase of the study (i.e. D1 and D2).

Exclusion Criteria:

• History of developmental, neurologic, or major psychiatric disorder resulting in functional disability.
• Contraindication or unwillingness to discontinuing sedating and centrally-active drugs (benzodiazepine, long-acting sedating drugs) within 48 hours of assessment.
• Upper limb contusions, fractures or flaccid paralysis.
• Uncontrolled epilepsy and already on level 1 drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Analgesic administration; The analgesic treatment will be tailored to the patient's medication and will be based on 3 levels (based on Ventafridda et al., 1985): Level 1 : Non-opioid analgesics; Level 2 : Weak opioids analgesics; Level 3 : Strong opioids analgesics If the patient is already on pain medications, we will add the lowest effective dose of the level above the level of the regular pain medications of the patient. (e.g. if the patient has no analgesic treatment, he will be given a non-opioid analgesic (level 1). If he already has a level 1 treatment, we will go for level 2 medication. If he has level 2 treatment, we will go for level 3. And if the patient is already at level 3, we will increase the dosage by steps (reference: 5mg oxycodone as first choice for level 3 drugs)). Preferably, the medication will be administered by oral intake or gastrostomy feeding tube. If it is not possible, other routes of administration are allowed.	Drug: Analgesic administration; Level 1 : Paracétamol 1g/Acetaminophène 1g, Ibuprofène 600mg, Diclofénac 50mg.; Level 2: Tramadol 50mg.; Level 3: Oxycodone 5mg, Morphine sulfate 10mg.; Increase of a prior level 3 medication :1/6 of the total dose of daily level 3 medication (e.g. the patient receives 30mg of oxycodone a day. He will be administered a single dose of 5 mg for the study), defined as a breakthrough dose in the management of chronic pain. To standardize the treatment, the dose of the prior level 3 medication will be converted to oxycodone. Several online tools exist to do the conversion between opioids (e.g. mobile app Orthodose ®).If the oral intake or the gastrostomy use is not possible, the breakthrough dose will be administered by subcutaneous route. The dose will also be 1/6 of the daily dose and will be converted to injectable morphine. Conversion to injectable morphine will be performed with any equivalence tool (such as the mobile app Orthodose ®)
Placebo Comparator: Placebo administration; Folavit capsules will be used as a placebo	Drug: Placebo administration; Folavit (folic acid, 0.4 mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nociception Coma Scale-Revised (NCS-R)	The NCS-R (Chatelle et al., 2012) is used to assess the perception of acute pain in patients with disorders of consciousness. It is composed of 3 subscales (motor, verbal and facial expressions) respectively scoring from 0 (no response) to 3 (highest response level). Here the NCS-R is administered in 4 different conditions: at rest, during tactile stimulation, during experimental nociceptive stimulation (pressure on the bed of the left and right nail) and during mobilization (physiotherapy).	through study completion, an average of 2 years
Coma Recovery Scale-Revised (CRS-R)	The CRS-R (Giacino et al., 2004) is the gold standard for the behavioural assessment of the level of consciousness and is widely used in patients with chronic disorders of consciousness. The CRS-R is composed of six subscales that assess the following domains: visual, motor, auditory and oro-motor/verbal functions, as well as communication, and arousal. The score ranges from 0 to 23, in which the lowest score indicates coma and the highest score indicates the emergence from the minimally conscious state. The diagnosis is made according to the presence\absence of particular behavioural responses.	through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Ashworth Scale (MAS)	The MAS (Bohannon et al., 1987) is used to assess spasticity (reflex contraction in response to passive stretching). This is a scoring scale from 0 (no increase in muscle tone) to 4 (very strong increase in tone, stiffness), which will depend on the speed of execution of the movement (the faster the limb will be mobilized the more spastic it will be) and which must be performed at least 3 times for each joint.	through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: University of Liege
• Investigators: Study Director: Steven Laureys, M.D., P.h.D, Centre du Cerveau, Coma Science Group (GIGA Consciousness)

Publications and helpful links

General Publications

• Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil. 2004 Dec;85(12):2020-9. doi: 10.1016/j.apmr.2004.02.033.
• Chatelle C, Majerus S, Whyte J, Laureys S, Schnakers C. A sensitive scale to assess nociceptive pain in patients with disorders of consciousness. J Neurol Neurosurg Psychiatry. 2012 Dec;83(12):1233-7. doi: 10.1136/jnnp-2012-302987. Epub 2012 Aug 20.
• Ventafridda V, Saita L, Ripamonti C, De Conno F. WHO guidelines for the use of analgesics in cancer pain. Int J Tissue React. 1985;7(1):93-6.
• Bohannon RW, Larkin PA, Smith MB, Horton MG. Relationship between static muscle strength deficits and spasticity in stroke patients with hemiparesis. Phys Ther. 1987 Jul;67(7):1068-71. doi: 10.1093/ptj/67.7.1068.

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2018
• Primary Completion (Actual): February 19, 2019
• Study Completion (Actual): April 28, 2021

Study Registration Dates

• First Submitted: March 9, 2020
• First Submitted That Met QC Criteria: March 30, 2020
• First Posted (Actual): April 1, 2020

Study Record Updates

• Last Update Posted (Actual): May 3, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Pain; Nociception; Disorder of Consciousness; Nociception coma scale revised
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Wounds and Injuries; Neurobehavioral Manifestations; Neurocognitive Disorders; Brain Damage, Chronic; Craniocerebral Trauma; Trauma, Nervous System; Unconsciousness; Disease; Brain Injuries; Consciousness Disorders; Persistent Vegetative State; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Analgesics
• Other Study ID Numbers: 2019-86; 2009-241 (Other Identifier: University hospital-faculty committee)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No