The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
Condition: Cerebral Palsy; Post-operative Pain
MeSH terms: Paralysis; Cerebral Palsy; Pain, Postoperative
Study type: Interventional
Phase: Phase 3

Summary: 
      Cerebral palsy is common. It affects approximately 3 per 1000 children. Hip displacement due
      to muscle tightness (spasticity) occurs in up to half of the more severely affected children,
      and many of these children require major (bony) hip surgery. After bony hip surgery the
      management of pain is very difficult, as spasticity tends to increase and causes painful
      spasms which are difficult to control. Botulinum Toxin injections are known to reduce
      spasticity and therefore should also reduce pain. These injections take at least a week to
      work, but the effects can last for months. Botulinum Toxin is already an established
      treatment for chronic hip pain prior to surgery. The investigators aim to find out whether
      Botulinum Toxin injections can reduce post-operative pain. The identification of the level of
      pain can be challenging because most of these children are unable to communicate verbally.
      The investigators are therefore using a validated pain scoring tool that was designed
      especially for such children. This study will be the first to describe fully the pain
      experience of children with cerebral palsy undergoing this type of major surgery. The
      investigators will compare Botulinum Toxin injections with placebo (non-active) injections.
      There is a high emotional and financial burden on the families of these children. Families
      describe high levels of emotional distress around the time of surgery, particularly when
      their child is in pain. Difficulty with pain control post operatively may delay discharge
      from hospital and parental return to work. It causes disrupted sleep for the child and family
      and may delay the child's return to school. The results of this study will be shared with
      professionals and families at international conferences and in scientific and popular
      (patient-based) publications. This study cannot be undertaken in adults with cerebral palsy
      as they only rarely undergo this sort of surgery.
    

Detailed description: 
      Botulinum toxin injected intramuscularly is beneficial in the management of spasticity and as
      a treatment for chronic hip pain in children with cerebral palsy. Botulinum injections also
      seem to be useful in reducing spasticity in the acute post operative period; the benefits of
      botulinum toxin have been described in one study for post-operative pain following minor hip
      surgery. After major (bony) hip surgery these children experience significantly more pain,
      which also seems to be exacerbated by spasticity. Botulinum toxin may therefore reduce pain
      following major hip surgery. Research is required to assess its value in this setting. This
      cannot be studied in adults as they rarely undergo such surgery.

      Cerebral palsy (CP) is the commonest cause of physical disability in childhood, it affects up
      to 3 children per 1000 throughout Europe (1;2). The Gross Motor Function Classification
      System (GMFCS) was designed for children and describes their level of motor skill (3). Over
      25% of children with CP probably fall in the more severely affected groups - GMFCS levels IV
      and V. These children are not independently ambulant and are more likely to have cognitive
      and communication difficulties. They are at high risk of developing hip displacement (ie the
      hip gradually comes out of its socket) (4-10). Previous studies suggest that up to half of
      these hips are painful and it is well-established that hip displacement is painful for some
      children (14-18). Prevention of painful hip displacement has been advocated through screening
      programmes and timely surgical intervention (11-13). Some children need bony reconstructive
      surgery. Long term follow up studies have demonstrated that this maintains the position of
      the femoral head in the acetabulum over time, reducing the likelihood of a painful hip due to
      dislocation (9;10).

      The management of pain in the severely neurologically impaired child undergoing hip (or any
      other) surgery is challenging and various strategies have been employed, including the use of
      post-operative epidurals. In a child with spasticity abnormally high post-operative muscle
      tone may be a cause painful muscle spasms. These involuntary and sustained muscle
      contractions are thought to contribute significantly to pain in children with cerebral palsy
      and a hip problem. There are a number of treatments available for muscle spasm in cerebral
      palsy; all are systemic except botulinum toxin which targets individual muscles by means of
      intramuscular injection. Botulinum toxin type A (BTXA) injection is a well established,
      clinically effective and safe treatment for muscle spasticity in CP (2;19;20). Research
      suggests it may have a beneficial effect in reducing pain due to spasticity (18). Graham and
      co-workers established that BTXA was safe in the perioperative period for children with
      cerebral palsy undergoing soft tissue surgery for a hip problem. Lundy and Fairhurst
      demonstrated BTXA is safe and effective in children with severe cerebral palsy, GMFCS IV&V
      when doses are given in line with the European Consensus guidelines. (24) Work on pain in
      children with CP suggests that anxiety and unrelieved pain may stimulate the autonomic
      nervous system in such a way that these children may actually have an amplified pain response
      when undergoing surgical procedures. Actions such as stretching muscles in a cast or for
      rehabilitation exercises may exacerbate spasms and therefore increase pain (8;17;21).

      Describing pain in children with cognitive impairment however is challenging. Studies have
      focused on the report of pain symptoms, duration, intensity and analgesia requirements. Hunt
      et al provided a validated pain profile questionnaire which objectively measures pain in the
      more severely neurologically affected group of children with communication difficulties (22).
      The investigators have gained experience using this Paediatric Pain Profile to describe
      levels of pain in this group of children. It is a validated and user friendly system, already
      in place at this institution.
    

Intervention name(s): botulinum toxin intramuscular injection
Intervention type(s): Drug
Intervention description(s): A single dose of active drug or placebo will be administered immediately prior to surgery.
The injections will be given to the anaesthetised child before the surgical procedure begins. The surgeon will perform the injections at three muscle groups around each hip: the adductors, hamstrings and iliopsoas muscles. Two units per kilogram will be given at each site. The maximum dose will be 12 units per kilogram or 500 units in total (whichever is the lesser), divided equally between six or three sites. Each active drug vial will contain 100 iu of the Botox preparation. The volume injected will be dependent on the weight of the child. Injections of normal saline will be administered in those children randomised to the placebo.
Other intervention name(s): Botox, Allergan.
Intervention MeSH terms: Botulinum Toxins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Cerebral Palsy; Hip displacement; Hip surgery; Post-operative pain; Botulinum Toxin