The purpose of this study is to determine the extent to which analgesic tolerance develops in
chronic pain patients who are either started on opioids or who receive an increase in
pre-study opioid dose level and then observed during long-term (20 weeks) stable opioid
therapy. In addition to clinical measures of relief of ongoing chronic pain, estimation of
tolerance development will be supplemented by periodic assessment of the anti-nociceptive
effects of opioids using the brief thermal sensitization model.
Minimum age: 21 Years.
Maximum age: 80 Years.
1. Adults who are 21-80 years of age.
2. Desires opioid dose increase (with approval of current prescribing physician), or is
not on opioids and desires a trial of opioids for ongoing pain.
3. Expected to remain in stable health for at least a six months period surrounding study
4. Able and willing to provide written informed consent.
5. Able to understand and follow the instructions of the investigator, including all
6. Stable chronic pain that is either neuropathic or non-neuropathic in origin as defined
above. The diagnosis will be based on history, physical examination, and review of
medical records confirming the diagnosis.
7. For a chronic user: stable opioid use of between 31 and 150 mg/day morphine
equivalent. Stable use is defined as no change in the daily dose of opioids for the
month preceding study entry.
8. For naïve users: have not used opioids or use is less than or equal to 30 mg/day
morphine equivalent for their chronic pain.
9. Chronic pain must be at least moderately severe, defined as an average daily pain
severity exceeding 40 mm on a 100 mm pain intensity visual analog scale (VAS).
10. Female subjects must be post-menopausal, physically incapable of becoming pregnant, or
using acceptable birth control method. Acceptable methods of birth control include
hormonal contraceptives or double-barrier methods (condom or diaphragm with
spermicidal agent or IUD). If practicing an acceptable method of birth control,
confirmation of negative pregnancy urine test for female subjects is required at the
Screening Visit. No special precautions are required for male subjects because
levorphanol is an approved therapy for chronic pain.
1. Use of opioid mixed agonist-antagonists (pentazocine, buprenorphine, butorphanol), or
tramadol, will not be allowed. Use of an intrathecal opioid infusion pump will not be
2. Allergy to levorphanol.
3. Patients who are unable to read or speak English.
4. A pain complaint, which is believed to be psychogenic in nature or cannot be confirmed
by medical records and physical examination.
5. Pain due to a disease, such as cancer not in remission, which is expected to
substantially progress during the study period.
6. Cognitive impairment, psychiatric disorder, or unrelated neurological disorder severe
enough to interfere with assessment of pain and sensory systems.
8. Has received an investigational drug within 30 days prior to Study Visit 2.
9. A current substance abuse disorder, a positive urine drug screen, or a history of
opioid drug abuse at any time in the past.
10. Intolerable side effects, or failed to achieve adequate analgesic effect during prior
attempts at opioid dose escalation within the range of doses to be used in this
11. Co-existing medical conditions or required medication use that contraindicate study
procedures or opioid dose escalation. Subjects with disorders, such as unusual skin
fragility or severe peripheral neuropathy that contraindicate brief thermal
sensitization will be allowed to participate without this component.
12. Those, in the opinion of the investigator, who are unlikely to comply with the study
protocol or who are unsuitable for any other reason.