A randomised, double blind, placebo controlled crossover trial of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model - an enriched population trial

Research summary

Patients with chronic neuropathic pain complain of pain in the absence of a painful stimulus. These spontaneous sensations can be constant and burning or intermittent and sharp or stabbing in quality. Pain can also be brought on by normally innocuous stimuli, such as the light touch of clothing, or gentle breeze against the skin, this is known as allodynia. Another feature is hyperalgesia, an increased sensitivity to mechanical pressure and thermal stimuli. We can mimic these symptoms and their underlying mechanisms in healthy volunteers using experimental models such as the capsaicin model, and investigate the effectiveness of analgesic drugs. These spontaneous sensations are likely to arise from ongoing neural activity, an explanation being that sensory pathways are hypersensitive and action potentials are generated too frequently. These frequent discharges are thought to play a fundamental role in initiating and maintaining the symptoms of hyperalgesia and allodynia in neuropathic pain.

Hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels are important modulators of action potential frequency. They drive repetitive electrical activity in heart pacemaker tissue and in some neurons by generating an inward current, Ih, following hyperpolarisation of the membrane, and so play a key role in neuronal rhythmicity. The HCN ion channel family comprises four isoforms, HCN1-4, which carry an inward current called Ih (also Iq or If). Ih is activated by hyperpolarization in the range of membrane potentials between -60 and -90mV, and the activation of this inward current is a major driver of the pacemaker potential in cardiac muscle. The dependence of the activation of HCN2 and 4 on membrane potential is shifted in the positive direction when cyclic AMP (cAMP) binds to a domain in the C-terminal tail, a shift which increases the inward current carried by Ih in the pacemaker region of membrane potentials and thereby mediates the chronotropic action of adrenergic agonists on the heart. HCN1 and 3, on the other hand, are relatively insensitive to cAMP. Ih is important in driving repetitive firing in some CNS neurons and also in primary nociceptive neurons.

Our hypothesis is that blocking HCN channels reduces hyperalgesia and allodynia in humans, in a healthy volunteer model that mimics the symptoms seen in chronic pain patients. The concept that HCN channels are involved in the establishment and perpetuation of neuropathic pain is novel and has been demonstrated in experimental animals. This study is very important because neuropathic pain is difficult to treat and places a great burden on individuals who suffer from it, their families and carers, and society as a whole. There has not been a new anti-neuropathic drug for more than 5 years. If ivabradine is helpful in reducing hyperalgesia in healthy volunteers (in an enriched population trial in which all the volunteers display a hyperalgesia in response to capsaicin), it strongly suggests that HCN channels are potential molecular targets for novel pain treatments. Not only could ivabradine be used to treat neuropathic pain, but more selective HCN blockers, without cardiac effects, could be developed.

This is a randomised, double-blind, placebo-controlled, 2-period cross-over trial in an enriched population of healthy volunteers who display a defined degree of hyperalgesia in response to capsaicin cream. The choice of a cross-over is justified by the fact that each volunteer will be its own control. A wash-out period of 3 weeks between Visit 1 (screening) and Visit 2 ensures a minimum 4 week wash-out period between Visit 1 and Visit 3 and therefore on the forearm used twice. This design ensures there is no residual sensitisation towards the capsaicin cream. We intend to recruit up to 42 healthy volunteers into the treatment phase of the trial (visits 2 and 3). We will only enrol those participants who are defined as capsaicinresponders (someone who has an area of punctate hyperalgesia on the forearm equal to or greater than 20cm2) as determined at the screening visit (visit 1). We anticipate approximately 40% of participants undergoing screening to be capsaicin-responders and continue into the treatment phase of the trial, and therefore anticipate screening approximately 150 healthy volunteers, assuming a capsaicin responder drop-out rate of no more than 30% during the trial. Screening will continue until up to 42 responders have fully completed all trial visits. We will allow the screening of any volunteer who previously participated in the IISNeP trial who we anticipate will be a capsaicin-responder from their previous results.

The brevity of the trial (approximately 4-8 weeks) will mitigate against volunteers dropping out, and therefore the cross-over design will allow subjects to provide their own control observations, thus increasing the accuracy of the treatment effect estimate, in comparison to a parallel-arms trial. The choice of an enriched population trial is justified by the preliminary evidence from the previous trial (IISNeP) that some volunteers do not respond to capsaicin cream application and therefore there was no window to see an effect of ivabradine. This method of screening for capsaicinresponders
and non-responders prior to the trial treatment phase of the trial has been reported previously. We expect around 40% of participants to respond to capsaicin as defined by the degree of sensitisation they display.


Main inclusion criteria

To be included in the trial the participant must:

  • have given written informed consent to participate

  • be able to communicate fluently in English

  • be male or female and aged 18-64 years

  • have absence of any chronic pain medicine

  • be in good general health with a Body Mass Index (BMI) between 19 and 35

  • normal resting multi-lead standard ECG including (measured for 1 minute on lead D2):

    • Normal sinus rhythm;

    • 60 bpm HR or greater on resting ECG;

    • PR interval ≤ 210 ms;

    • QTcB ≤ 430 ms for men and QTcB ≤ 450 ms for women;

    • QRS duration ≤ 120 ms;

The results of ECG recordings will be included in the CRF.

  • Women on the study who are of child-bearing potential must avoid becoming pregnant by taking adequate precautions with birth control for at least one month before the first drug dose and until one week after the final trial visit. These precautions include:

    • Intrauterine device (IUD)

    • Hormonal based contraception (pill, contraceptive injection etc.)

    • Double barrier contraception (condom and occlusive cap eg diaphragm or cervical cap with spermicides

    • True abstinence where it is in line with the participant’s preferred and usual lifestyle (no sexual activity from at least 1 month before the first drug dose until one week after the last trial visit). If women become sexually active they must use other methods listed above. Women who are post-menopausal, sterile or have undergone sterilisation are exempt from the above precautions.

  • Men must agree to use the following reliable forms of contraception from the first drug dose and until one week after the last trial visit:

    • A condom and spermicide even if female partner(s) is using another method of contraception. (Men should also use a condom to protect female partners from exposure to the study medicine in semen.)

    • True abstinence where it is in line with the participant’s preferred and usual lifestyle (no sexual activity with female partner(s) immediately after the first drug dose until one week after the last trial visit). If men become sexually active they must use the method listed above.

Main exclusion criteria

The presence of any of the following will preclude participant inclusion:

  • Volunteers with 1 arm

  • Pre-existing pain on either forearm

  • Previous surgery or tattoo on either forearm

  • History of disease associated with neuropathy

  • Volunteers who are allergic to ivabradine or capsaicin or any of the excipients within the respective finished products

  • History of personal or familial Long QT Syndrome

  • History of cardiac dysrhythmia

  • Use of CYP3A4 inhibitors such as ketoconazole, itraconazole, macrolide antibiotics and the anti-retrovirals nelfinavir, nefazodone and ritonavir.

  • Use of CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin or St John’s Wort etc.)

  • Use of QT interval prolonging medicinal products (e.g. quinidine, disopyramide or pimozide etc.)

  • Volunteers with any rash or broken skin on the arm where the capsaicin will be applied

  • Volunteers with lactose intolerance, as the placebo and ivabradine tablets contain lactose

  • Volunteers with a resting heart rate of 59 beats per minute or less at screening

  • Volunteers who are pregnant or breast feeding

  • Female volunteers of childbearing potential who refuse to use adequate contraceptive measures for the duration of the trial

  • Male volunteers who refuse to use adequate contraceptive measures for the duration of the trial

  • Volunteers who have an underlying medical condition such as migraine or epilepsy which may affect the trial findings

  • Volunteers who smoke (≥5 cigarettes/day), take recreational drugs or consume more than the recommended allowance of alcohol units per week (21 units per week for males and 14 units per week for females)

  • Participants who are not willing to abstain from drinking beverages containing quinine, caffeine and/or xanthine for 24 hours prior to the trial visit

  • Volunteers who produce a positive result in a urine screen for drugs or who are known or suspected to be drug-dependent (sedatives, hypnotics, tranquilizers or any other addictive agent)

  • Volunteers who produce a positive result in an alcohol breath test

  • Volunteers currently participating in any interventional trial, have participated in an interventional trial within 16 weeks of screening or are currently participating in a non-interventional trial which participating in this trial would impact upon

  • Volunteers who, in the opinion of the PI, have a clinically relevant abnormality or medical history that is deemed to make the participant ineligible because of a safety concern.

Chief investigator

Dr Michael Lee

Contact details

Clinical Trials ManagerDr Paula Kareclas

Telephone: 01223 596473 | Email: [email protected]