Propofol Injection for Daily Headache
Condition: Chronic Headache; Analgesic Rebound Headache; Chronic Daily Headache; Headache, Intractable
MeSH terms: Headache Disorders; Headache Disorders, Secondary; Headache
Study type: Interventional
Phase: Phase 2

Summary: 
      Hypothesis A single subanesthetic dose of propofol will result in improved pain and quality
      of life for the next 30 days in persons with chronic daily headache (CDH)

      Specific objectives To measure the effect of a single infusion of propofol at 40 mcg / kg /
      minute over 60 mins on headache-related quality of life (measured by the Headache Disability
      Index) and on headache severity (measured by the Headache Index) in subjects with chronic
      daily headache over 30 days45-47
    

Detailed description: 
      Chronic daily headache (CDH) is a common and extremely disabling pain syndrome with a recent
      estimated point prevalence of 2.98% of the general population1 Other studies estimate a
      prevalence of 4.1% and 4.7% with a higher prevalence in women of 9%.2,3 The condition is
      disabling and is a major cause of loss of function and work capacity resulting in significant
      personal and national economic loss4

      Therapeutic options for treating chronic headache disorders are legion and diverse and there
      is a steady stream of publications advocating novel therapies. Pharmacological options that
      have been advocated include: sodium valproate, olanzapine, tricyclic and Selective Serotonin
      Reuptake Inhibitor antidepressants, tizanidine, butalbital, nefazodone, baclofen,
      prochlorperazine, intravenous lignocaine, dihydroergotamine, opioids, monoamine oxidase
      inhibitors, triptans, botulinum toxin, cryotherapy and analgesic withdrawal5-20 There is much
      debate as to why headache treatments fail and it is proposed that the choice of an
      inappropriate agent is a significant reason in some patients21

      On the basis of a small number of studies intravenous propofol has now been advocated for the
      treatment of chronic daily headache22-24 It seems fair to conclude that the existing strife
      to promote propofol as an effective intervention for treating CDH in the absence of a
      randomized controlled trial merely reflects the lack of a single good treatment option for
      this condition. It is, furthermore, reasonable to speculate that the beneficial effect seen
      with propofol is a placebo response. Krusz et al reports the effects of subanesthetic doses
      of intravenous propofol on chronic migraine in a cohort of 77 subjects in an open-label
      study22 Propofol was administered by intermittent boluses; the average dose used was 110mg.
      It is reported that 63 out of 77 patients reported complete abolition of their headache with
      an average time of 20 - 30 minutes of propofol treatment. The range of propofol doses used is
      however not clearly stated and there was no assessment of the intervention beyond 24 hours.
      In this study lidocaine was mixed with propofol to reduce the pain of injection but it could
      not be said with any certainty that lidocaine itself has no effect on headache.

      Mendes et al retrospectively reports 21 independent treatments of propofol in 18 patients
      suffering primary and secondary chronic daily headache over a 1 year period 23 Subanesthetic
      doses of propofol were administered by intermittent intravenous boluses 20 - 30mg every 3 to
      5 minutes (range 60 - 380 mg). 6 patients reported complete relief of pain with the
      treatment, 1 patient had no pain relief; on average patients reported a 58.92% decrease in
      pain using a 0 - 10 scale. It is reported that 8 patients' headache cycles were broken when
      followed up several days later but no information is available on the longer term impact of
      these interventions. In these two studies there appears to have been good tolerance of
      propofol and no significant adverse events.

      Drummond - Lewis reports 2 hospitalized patients with refractory migraine who were treated
      with anesthetic bolus doses of propofol (0.5 - 1mg / kg) with reported success 24. The
      authors comment there is uncertainty as to the most effective dose of propofol for this
      treatment.

      Propofol is a safe modern, non-barbiturate intravenous anesthetic induction agent that was
      introduced into clinical anesthesia in 1977. It has established its place in practice because
      of its many ideal characteristics; it causes rapid and smooth loss of consciousness and rapid
      recovery, making it an ideal agent for day-case procedures25,26 There is extensive use of
      propofol as an intravenous sedative for procedures such as endoscopy, electroconvulsive
      therapy, cardioversion and for longer term sedation in the intensive care unit.27,28 Propofol
      has useful antiemetic properties and is known to be anti-epileptic and antipruritic.29
      Although propofol can cause pain on intravenous injection there are several strategies to
      reduce this problem.30 There are reports of rare fatalities associated with high doses of
      propofol and reports of pancreatitis after single doses.31,32

      Propofol (2,6 di-isopropylphenol) is available as an emulsion of 1 % propofol in 10% soyabean
      oil, 2% glycerol and 1.2% egg phosphatide. Doses up to 2.5mg / kg are used for induction of
      anesthesia and doses up to 200ug / kg /min are used for sedation purposes.33 It remains
      uncertain how propofol might exert its action in relieving headache. Propofol is known to
      stimulate gamma - aminobutyric acid- A (GABA-A) receptors by enhancing channel opening34 It
      has been shown that other GABA ergic drugs including sodium valproate, gabapentin and
      topiramate have a place in the treatment of migraine and it is speculated that propofol might
      be work in a similar way.35 Nonetheless, it is known that propofol has other important
      pharmacological activity including N-methyl-d-aspartate receptor antagonism, sympathetic
      inhibition, stimulation of nitric oxide production, calcium channel inhibition and modulation
      of prostaglandin E2 hyperalgesia.36-39 We propose that it is premature to speculate on the
      action of propofol in headache without clear evidence of efficacy.

      There is ongoing discussion as to what is a good definition of chronic daily headache; this
      is a term that is not defined by the International Classification of Headache Disorders
      (ICHD)40 This is a potential impediment to research. It has been proposed that chronic daily
      headache can be subclassified into primary headache that includes transformed migraine (TM),
      chronic tension-type headache (CTTH), hemicrania continua (HC) and new daily persistent
      headache (NDPH)41 Secondary CDH has an identifiable underlying cause e.g. post traumatic,
      cervical spine disorders, vascular disorders, chronic meningitis, idiopathic intracranial
      hypertension, temporamandibular joint dysfunction and sinus disorders. Silberstein et al
      highlighted that not all chronic daily headaches can be classified according to the ICHD;
      however, in 1996 they managed to completely sub-classified a population of CDH sufferers into
      those with transformed migraine (TM) 78%, chronic tension-type headache (CTTH) 15.3% and
      "other" 6.7%.42 Silberstein defined chronic daily headache as headaches that last for more
      than 4 hours a day for more than 15 days a month and this definition is used in their later
      study of propofol and headache. This definition becomes perhaps less crucial when dealing
      with a population of patients who suffer intractable continuous headache; this tends to be
      the characteristic of patients who are already known to us at the University of Alberta
      Hospital Pain Centre.

      Significance and importance Although it is reasonably argued that propofol sedation can be
      administered safely by non-anesthetists, there is still the possibility of serious airway
      complications and cardiorespiratory depression.43 The administration of propofol should not
      be undertaken lightly and certainly not used for an indication that has not been subject to
      rigorous trial. Previous studies of propofol and headache have only examined the short- term
      impact of this intervention on pain scores. The study proposed here looks at the effect of
      this treatment on pain and quality of life over a longer period - 30 days.

      If subanesthetic doses of propofol are found to be effective in reducing chronic daily
      headache we become armed with a relatively safe non- narcotic intervention for this extremely
      disabling disorder that could be provided at a variety of centres e.g., emergency rooms, pain
      clinics, neurological facilities. In view of the reluctance by some emergency departments to
      administer narcotics for chronic headache we speculate that emergency departments may be more
      willing to provide this treatment than narcotics.44

      Hypothesis A single subanesthetic dose of propofol will result in improved pain and quality
      of life for the next 30 days in persons with chronic daily headache (CDH)

      Specific objectives To measure the effect of a single infusion of propofol at 40 mcg / kg /
      minute over 60 mins on headache-related quality of life (measured by the Headache Disability
      Index) and on headache severity (measured by the Headache Index) in subjects with chronic
      daily headache over 30 days45-47

      Study Site

      The Chronic Pain Centre 1A1 Walter Mackenzie Health Sciences Centre, University of Alberta,
      Edmonton. Alberta, T6G 2B7. Tel: 780 407 8638.

      Methods Ethics approval for this study will be sought from the local institutional ethics
      board and Health Canada.

      Inclusion criteria

        -  Adult subjects (18-65 years) with CDH by the criteria of Silberstein and Lipton.41 i.e.
           on the basis of pre-randomization history suffer chronic headaches lasting more than 4
           hours a day for more than 15 days a month.

        -  Previously investigated to exclude serious treatable pathology.

        -  On the basis of the pre-randomization headache diary: the average pain intensity during
           each episode should be at least 5 /10 on the Numerical Rating Scale (NRS) on 4 days out
           of 7.

        -  Quality of life and function should be impaired as evidenced by a (pre-randomization)
           Headache Disability Index (HDI) of at least 40.

      Exclusion criteria

      History of the following:

        -  Known or suspected allergy to propofol, intralipid or midazolam,

        -  In emergency or life-threatening situations,

        -  Those having language barriers (e.g. illiterate, not English-speaking, dysphasic),

        -  Known or suspected difficult airway or sleep apnea,

        -  Severe respiratory disease,

        -  Neuromuscular disease,

        -  Seizure disorder,

        -  Severe cardiac disease,

        -  Severe gastresophageal reflux disease,

        -  Pancreatitis,

        -  Lipid disorders,

        -  Receiving Total Parenteral Nutrition,

        -  Body mass index > 35, diabetes or major endocrine disorder,

        -  Hepatic or renal failure,

        -  Unstable psychiatric disorder,

        -  Known drug abuse,

        -  Pregnancy,

        -  Cognitively impaired.

      Obtaining Consent Each subject will be given an information sheet describing the study
      procedures, offered the opportunity to ask any questions and must sign that they have
      understood the contents. A separate consent form will be signed by the participant. Any
      questions will be dealt with by an investigator. The headache diary and all information to be
      read by subjects will be designed to have a Flesch Kincaid reading age of less than or equal
      to grade 8. Subjects will be free to withdraw from the trial at any stage.

      Pre-randomization - baseline data collection

        -  Demographic data to include: age, gender, education level (years), and socioeconomic
           status.48

        -  The features of the subject's headache will be recorded and the headache disorder will
           be classified according to the International Classification of Headache Disorders.40 The
           date of chronic headache onset will be recorded.

        -  A standard medical history will be recorded which will include details of current
           medication, (specifically headache medication) and stage of menstrual cycle.49

        -  A physical examination will be performed. Pulse, non-invasive blood pressure,
           respiratory rate, oxygen saturation from pulse oximetry, weight, height and temperature
           will be recorded.

        -  Subjects will then complete the Headache Disability Inventory (HDI).45

      Headache Diary

      • Participants will then be instructed in the completion of the daily headache diary (this is
      estimated to take 10 - 20 minutes). This diary will keep track of daily pain scores,
      activity, headache medication use and visits to the emergency room. Headache severity is
      recorded four times daily on an 11 point numerical rating scale (NRS) anchored at zero for no
      pain and 10 for the worst imaginable pain. Participants will be asked to keep this diary for
      7 days pre-randomization and for 30 days commencing the day after the treatment / infusion.

      Randomization and blinding Subjects that still meet the inclusion criteria will proceed to
      the treatment phase. Subjects will be assigned to either the propofol group or placebo group.
      Sealed envelopes containing a randomized assignment to either propofol or placebo group will
      be prepared by an individual unconnected with the study using a web-based random number
      generator, and balanced to ensure equal allocation to each group. The propofol group will
      receive propofol and a concurrent normal saline bolus. The placebo group will receive
      intralipid and an identical concurrent normal saline bolus that contains low dose midazolam.
      There is evidence that low dose midazolam (35 mcg / kg) is sufficient to produce adequate
      sedation but no evidence to support the use of single dose midazolam as a treatment for CDH;
      this makes midazolam a suitable choice as an active placebo.50 The use of an active placebo
      is to minimize treatment recognition and bias by patient and investigator. Identical,
      sequentially numbered syringes containing either propofol or intralipid will be prepared by
      the hospital pharmacy and these will be appropriately coupled with identical numbered
      minibags of saline containing either no drug or midazolam. Subjects will be randomized after
      inclusion and exclusion criteria have been applied. Investigators will use these syringes /
      minibags in numeric order. (The named contents of each syringe and minibag will be available
      to the investigators in a second sealed envelope to be opened only in case of emergency
      during the infusion). Subject data will be grouped by treatment allocation for analysis into
      'Group A' and 'Group B', but the blind will not be fully broken until data analysis is
      complete. The subject's daily pain diaries will be coded with the corresponding syringe code.

      Infusion procedure On the day of participation the participant will be required to be fasted
      from the previous midnight. The groups will receive the following treatments by electronic
      infusor. The dose of propofol selected is comparable with that of the previous studies.22-24

      Active treatment

        -  Propofol infusion 40 mcg / kg / minute over 60 minutes coupled with a

        -  concurrent infusion of saline in a minibag to be delivered at 1ml / kg over first 10
           mins.

      Placebo group

        -  Intralipid by infusion, calculated to be delivered at the same rate as if it were
           propofol coupled with a

        -  concurrent infusion of saline in a minibag containing 35mcg / ml of midazolam to be
           delivered at 1ml / kg over the first 10 mins.

        -  To minimize pain on infusion (that may occur with either treatment) a large vein
           (preferably antecubital) will be cannulated.

      Environment and Treatment The location of the study will be the treatment suite of the
      University of Alberta Hospital Pain Centre. At least one anesthesiologist will be on site and
      a post anesthesia recovery nurse. A peripheral intravenous cannula will be inserted into each
      participant and intravenous normal saline 250 cc will be commenced to run over one hour in
      conjunction with the treatments to flush the intravenous line. The patient will be placed on
      a stretcher and made comfortable within the privacy of the suite. The lighting may be dimmed
      but not to a level that would compromise monitoring and safety. Noise will be kept to a
      minimum.

      Monitoring and Safety Non-invasive blood pressure will be recorded pre-infusion and then at 5
      minute intervals in conjunction with continuous pulse oximetry and respiratory rate. Oxygen
      via nasal cannulae to keep oxygen saturations at or above 94% will be commenced. Basic and
      advanced life support equipment will be available in the suite. An investigator, a trained
      anesthesiologist with extensive experience in the administration of propofol and qualified in
      resuscitation, will be in constant attendance.

      The infusion will be discontinued if the patient develops signs of respiratory depression (<
      8 breaths / min), requires more than simple maneuvers to maintain the airway, develops
      oversedation or delerium - where a patient is not easily roused by verbal command, sustained
      hypotension, oxygen desaturation (below 94%), cardiac dysrhythmia or new medical symptoms. In
      the event of the development of any adverse reaction a referral to the relevant specialist
      service within the University of Alberta Hospital will be available. Patients will be
      observed for a period of two hours post infusion and will be free to leave the suite when
      their vital signs are stable, there are no concerns about level of consciousness and the
      patient meets the University of Alberta Hospital criteria for discharge form day- surgery.
      Full recovery from either infusion is anticipated to take less than two hours.51 The patient
      must be escorted home and must be in the company of a carer for 24 hours. The patient will be
      instructed not drive or operate heavy machinery for 24 hours post infusion.

      Data Collection. Baseline data will be recorded as above (including HDI and Headache Diary).
      Pain, nausea and sedation scores will be recorded pre-infusion and then immediately post
      infusion Each subject will be given a daily headache diary to keep for the 30 days following
      the infusion. Subjects will be contacted by telephone at 24 and 72 hours post infusion and
      weekly thereafter to remind them to complete their headache diaries. At 30 days post-infusion
      the patients will complete a follow-up HDI by telephone or mail and their diaries collected.

      Outcome measures. The primary study outcome will be Headache Disability Index and the
      Headache Index45-47 The baseline Headache Index is the mean of all 28 NRS pain scores (four
      measures daily for seven days) and the post-treatment Headache Index is the mean of all 120
      NRS pain scores (four measures daily for thirty days) and provides a valid summary measure of
      overall headache activity.

      Secondary outcome measures will include:

        -  Number of days with a headache of at least moderate severity defined as pain at least 5
           on the Numerical Rating Scale (NRS).52

        -  Peak daily headache severity according to the NRS.

        -  Analgesic medication consumption will be measured in terms of morphine equivalents of
           narcotic medication and number of tablets /doses of acetaminophen / non-steroidal
           anti-inflammatory (NSAID) containing analgesics.53

        -  Visits to the Emergency Room for headache treatment.

        -  Sedation and nausea scores in the treatment and placebo groups.

        -  Ability of participants in each of the groups to correctly guess their treatment
           assignment.

        -  Adverse effects related to the infusion.

      Power calculation

      Mean HDI measurements of 60 (+/- 20) for severe CDH (the population toward which our clinic
      population is biased) would be expected. A clinically significant outcome would be a 29 point
      reduction of HDI. A sample size of 20 subjects will give 80% power to detect this difference
      with an alpha error rate of 0.05.

      Analysis Between group demographic factors that will be examined and controlled for will
      include age, gender, education level (years), and socioeconomic status using independent
      samples t-tests.48 All analyses will be conducted on an intention to treat basis. The average
      absolute difference between the baseline and post-treatment HDI scores for the two infusion
      groups will be compared using analysis of variance (ANOVA). We will compare the changes in
      NRS scores between the two infusions groups over time using repeated measures ANOVA. Any
      demographic factors found to be significantly different between groups will be included as
      covariates in this analysis. All t-tests will use Bonferroni corrections to control for the
      inflation of alpha.
    

Intervention name(s): Propofol
Intervention type(s): Drug
Intervention MeSH terms: Propofol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Chronic Headache; Analgesic Rebound Headache; Chronic Daily Headache; Headache, Intractable; Randomised controlled trial; Propofol