Safety and adverse event outcomes

Both clonidine and pentoxifylline have a history of safe systemic use in humans, and there is evidence that topical application of these agents produces extremely low to undetectable plasma levels [27]. As no negative effects were observed in animals or adverse effects in our trial in healthy volunteers, we do not anticipate any adverse side-effects with our topical treatment [25, 28].

According to the FDA, rare events in patients taking pentoxifylline (although not established as caused by the drug) include anaphylactic reactions [32]. Subjects will be asked to immediately report any signs of anaphylaxis (itchy rash, lip or throat swelling) to the study coordinator, who will instruct the patient to go immediately to a hospital emergency room.

Risks involved in taking clonidine orally are dizziness, light-headedness, drowsiness, tiredness, and vision problems, which are caused by a decrease in blood pressure [33]. Patients will be asked to immediately report any of these symptoms to the study coordinator, who will instruct the patient to see the study physician, who will perform a medical evaluation, including assessment of blood pressure. If any subject’s systolic pressure is found to be below 80 mmHg, they will be asked to stop the treatments and will be removed from the study. Abrupt discontinuation of clonidine can occasionally result in a withdraw syndrome, characterized by a rebound increase in blood pressure and other symptoms and signs of sympathetic activity like restlessness, increased heart rate, and increased irritability [34]. This usually occurs after cessation of large oral doses and in some instances after transdermal treatment. There is minimal risk for this syndrome with our study drug, as the dose of clonidine used is much lower than oral or transdermal preparations. Patients will be asked to report to the study coordinator if any of these symptoms occur during the washout period of the study and the few days following completion of the study. Clinical evaluation and appropriate medical care will accordingly be provided.

All adverse events will be tabulated, summarized, and reviewed by the study physician. Serious adverse drug reactions, i.e., reactions causing hospitalization; persistent or significant disability; that is life-threatening or resulting in death, will be immediately reported to the study sponsor who is the primary investigator and the research ethics coordinator for the study site. Serious adverse drug reaction reporting will follow International Council for Harmonization (ICH) guidelines.