Compare the Efficacy and Safety of Intranasal Esketamine in Chronic Opioid Refractory Pain

Inclusion Criteria:

* Patient with refractory cancer pain, this pain defined when:

  * Multiple evidence- based biomedical therapies used in a clinically appropriate and acceptable fashion have failed to reach treatment goals that mainly include adequate pain reduction and/or improvement in daily living functioning activities.
  * Patients' functional activities do not allow a quality of life which is acceptable and/or pharmaceutical therapies have resulted in intolerable adverse effects.
* Psychiatric disorders and psychosocial factors that could influence pain outcomes have been assessed and appropriately addressed
* Cancer pain classified as chronic (persistent or recurrent pain lasting longer than 3 months), and currently refractory despite optimized analgesic therapy including an opioid.

  • Optimized analgesic therapy is arbitrarily defined as: oral morphine equivalent of 60 mg/d or more (or another strong opioid at optimized dose) plus at least one adjuvant analgesic drug, for at least 2 weeks.
* No increase in baseline long acting opioid dose or addition of a new adjuvant analgesic drug within 2 weeks prior to study entry
* Ability to communicate the intensity of pain using the NPRS pain scale ranging from (0 as no pain to 10 with severe pain).
* Ability to give fully informed written consent.
* Expect survival more than 3 months.

Exclusion Criteria:

* History of allergy or intolerance to esketamine or ketamine.
* History of allergy to disinfecting products containing quaternary ammonium, who might be susceptible to be allergic to denatonium benzoate.
* Concomitant use of xanthine derivatives (e.g. aminophylline, theophylline), ergometrine, or monoamine oxidase inhibitors.
* Active nasal/sinus dysfunction (e.g. allergic or infectious rhinitis) or presence of any lesion of the nasal mucosa.
* Pregnancy, breastfeeding and women of childbearing potential not using a highly effective contraception method.
* Uncontrolled hypertension, arrhythmia, heart failure, or untreated coronary artery disease. History of transient ischemic attacks, stroke, neurovascular disease, hemorrhage, severe head injury, hydrocephalus or elevated intracranial pressure within the last 3 months.
* History of primary or metastatic malignant brain lesions (uncontrolled or without previous treatment).
* Known aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation
* Uncontrolled psychiatric illness with psychosis/ hallucination (e.g. schizophrenia, acute psychosis).
* Alcohol abuse, drug abuse/ dependence within the past 6 months as self-reported.
* Cirrhosis or severe hepatic impairment defined as 5-fold elevation of transaminases
* Uncontrolled hyperthyroidism.
* Globe injuries or increased intraocular pressure (e.g. glaucoma).
* History of ulcerative or interstitial cystitis.
* Subjects scheduled to receive radiotherapy (RT) to a site of pain during the study period, or who have received RT to a site of pain within 2 weeks before study entry.
* Subjects scheduled to undergo surgical treatment during the study period likely to affect pain.
* Subjects on or starting chemotherapy if there is a significant expectation of that therapy affecting pain.
* Subjects who have not provided signed informed consent form.
* Concomitant use of drugs moderately or severely affecting cytochrome P450 activity.