Simultaneous Use of Stimulants 
and Opioids

Stimulants should be added to a chronic opioid regimen to maximize pain relief and prevent opioid complications. By Forest Tennant, MD, DrPH 

It’s a puzzling situation. History and science are pretty clear: the simultaneous use of stimulants and opioids have, for over a century, been reported to be a superior combination for pain relief. 1 So, based on history, why isn’t every patient who’s taking opioids also taking a stimulant? For example, in 1977 the renowned analgesic researcher, William Forest, led a national cooperative study which clearly showed that a dose of dextroamphetamine with morphine increased morphine’s pain-relieving potency one and a half to two times. 2 Forest and colleagues posited that the great therapeutic benefit of the combination of dextroamphetamine and morphine wasn’t widely used because, “We suspect that the combination has not been accepted clinically at least, in part, because physicians do not want to subject their patients to the risk of abuse if these drugs (dextroamphetamine and morphine) are used.”


Although these pioneering researchers lamented the non-use of this combination in their seminal study, it turns out that they may, after all, get their wish. Sophisticated pain practitioners everywhere are starting to use various combinations of stimulants and opioids to enhance their pain therapeutics. What’s more, all parties concerned—including those who foot the bill—are benefitting. 


An Old History of Use and Effectiveness


It has been long-established that amphetamines and other stimulants have an analgesic effect in their own right and significantly enhance the analgesic effects of opioids. 1-9 The first person to suggest this combination was probably Dr. Herbert Snow of London (in 1896) who recommended an oral mixture of morphine and cocaine for patients suffering in agony from an advanced disease. 1 In the 1920s, the “Brompton Cocktail” was invented at the Royal Brompton Hospital in London. 1 The cocktail consisted of morphine or diacetylmorphine (heroin), cocaine, ethyl alcohol, and chlorpromazine (e.g., Thorazine ® ) for nausea. It was usually reserved for terminally ill patients with cancer or tuberculosis. Dextroamphetamine and morphine were found to be an excellent combination for pain relief during World War II. 3 Also, during this war-time period, it was found that stimulants would counteract the respiratory depression and sedation of opioids. 4,5 Although the use of this combination was known, it was seldom used clinically and essentially unreported in the medical literature after the war. Instead, researchers, commercial producers, and practitioners turned their attention to combining stimulants, including caffeine, into single commercial products. 6-8 This interest led to the development of popular combination drugs consisting of weak stimulants with opioids and/or inflammatory agents. The combination products of codeine with aspirin or acetaminophen and caffeine are widely known and have been highly prescribed for over two generations.


Although not yet widely adopted, a number of excellent studies on stimulants and opioids were done between 1950 and the end of the last century. 10-16 All of these studies—whether done in animals or humans—showed remarkable enhancement of pain relief when stimulants were combined with opioids. 8-14 One of the surprising and positive finding in these studies was that stimulants not only gave better pain relief but subjects (animals and humans) routinely performed mentally and physically better and had less respiratory depression and sedation than with opioids alone. 15-19 Clinical studies outside the seminal study by Forrest et al 2 are sparse but those that have been reported show the significant advantage of the simultaneous use of opioids and stimulants. 10,17 Even obstetrical analgesia is enhanced by this combination. 20 


Why a Need for Stimulants?


The “Decade of Pain” has brought opioids to the forefront of chronic pain treatment. It is estimated that about 10 million patients in the United States now use them. The exposure of millions to opioids has given us a population of patients who now know that the opioid class of drugs is indispensable for their pain relief. Although hardly news, practitioners, patients, and families are now beginning to observe the complications of opioids including sedation, fatigue, mental dullness, constipation, falls, and hormone suppression. Since no caring practitioner or patient who experiences pain relief with opioids is about to give them up, a stimulant added to the opioid regimen can enhance pain relief, limit opioid dosage, and prevent some opioid complications.


Mechanism Of Action


Too often it is perceived that the endogenous endorphin-opioid receptor system is the only pain control mechanism in the central nervous system. 21,22 In reality, multiple neurochemical systems are at play in pain relief. 22 They include, among others, the serotonergic, gamma-amino-butyric acid (GABA-ergenic), and adrenergic (norepinephrine-dopamine)systems. 8,21-23 Pain relief with stimulants appears to be primarily mediated by norepinephrine and not dopamine. 23 It is the simultaneous triggering of the endorphin and adrenergic neurochemical systems that gives the combined administration of opioids and stimulants a pain-relieving effect much greater than either one alone. 8,13,17 


Obvious Benefits


When a chronic pain patient on opioids adds a stimulant to their regimen, they and their observing family usually note less fatigue and lethargy and accompanied by intellectual awakening and more energy. Patients will frequently report less depression, better memory and more intense concentration ability (see Table 1). Enhanced pain relief may occur with the first dosage of stimulant. Stimulants can also lower an opioid daily dosage and ease the discomfort of opioid rotation or forced withdrawal due to loss of financial support of an expensive opioid.


How To Administer


Stimulants generally fit a dose response curve. They are not effective until the dosage reaches a specific level for a patient’s specific need. For safety, start with a low dosage and titrate upward over four to eight weeks until a therapeutic effect is reached. Stimulants can be given on their own fixed schedule such as two or three times a day or they can be simultaneously given with an opioid dosage. Table 2 presents several tips on how to administer stimulants.


Unanswered Questions


The use of stimulants with opioids, while historic, has been a seldom-used procedure in contemporary medicine. 2Consequently, there are some unknown questions that will require some tincture of time and some observant physicians to provide answers. First, what should the dosage be? Given the plethora of toxic reactions being served up by the methamphetamine-abuse epidemic, caution is advised. No one really knows what methamphetamine dosages are used by street abusers, so it is impossible to compare street dosages with low dose prescription products. A recommended course with a selected stimulant is to start low in dosage and titrate upward over time. For example, I like to start dextroamphetamines at one of the two lowest commercial dosages, 5 or 10mg, two or three times a day. I initially start phentermine at 30 or 37.5mg once or twice a day. The second unanswered question is whether we will see long-term toxic complications of stimulants. Reports to date indicate that stimulants have negligible effects on blood pressure, heart rate, or mental abilities. 2,17,18 The third unanswered question is therapeutic tolerance. Will patients who find a stimulant-opioid combination to be effective later find out that tolerance sets in and effectiveness vanishes? No one really knows. I have now had patients on stimulant-opioid combinations for over two years, and the stimulants continue to appear safe and effective with no toxic complications. 


Abuse Caution


All available stimulants, with the possible exception of caffeine, have some abuse potential. For this reason, the author recommends that stimulants only be prescribed to chronic pain patients who are known to the practitioner to take their opioids in a responsible, non-abuse fashion.


Side-Effects


Stimulants in a chronic pain patient who takes opioids have a negligible effect on blood pressure and pulse rate. In the author’s experience, stimulants taken too close to bedtime may cause insomnia. The toxic reactions, psychosis, hyperthermia, weight loss, and violence that are observed in street methamphetamine-abusers have not been reported with the prescription stimulants used with opioids. Despite millions of dosages prescribed over three decades in appetite suppressants used for obesity, there have been remarkably few claims of addiction. 24 


Available Stimulants


The stimulants most used with opioids have been dextroamphetamine and methylphenidate. 17-19Phentermine and phendimetrazine are old-time stimulants normally used for weight control. They are amphetamine derivatives with little abuse potential, low cost, and yet are effective opioid potentiators. The newest prescription stimulants are combinations of amphetamine derivatives and modafinil (Provigil ® , Nuvigil ® ). A summary of available stimulants is presented in Table 3.


Case Reports


Practitioners will find that the addition of a stimulant can help in a number of situations involving patients who take opioids. For example, there are patients who don’t wish to take opioids or who wish to at least maintain a low opioid dosage. Other opioid patients may lose health plan coverage and be forced to switch from an expensive opioid to a new regimen. Practitioners may simply want to lower an opioid daily dosage because they perceive it to be too high or producing a complication such as hormone suppression.


Case 1. Avoiding a Long-Acting Opioid


A 39-year-old, active-duty law enforcement officer weighed over 275 pounds and had degenerative spine and hip disease. He was taking a hydrocodone/acetaminophen combination in a dosage of about 80mg of hydrocodone a day. He resisted taking long-acting opioids or raising his opioid dosage. He was given phentermine 30mg twice a day that gave him about 25% more pain relief. This was enough to enable him to work full time and function well. As an added benefit, he lost 20 pounds.


Case 2. Forced Removal of a Long-Acting Opioid


A 57-year-old male severely injured his lumbar spine while parachuting. He controlled his pain quite well for several years with long-acting oxycodone. He lost many of his insurance benefits and could not afford to purchase long-acting oxycodone. He was switched to a less expensive regimen of a fentanyl transdermal patch (25mcg/hr) and phentermine 37.5mg twice a day. He claims this regimen is as effective as his previous one. 


Case 3. Cytochrome P450 Abnormality


A 62-year-old female had degenerative spine disease with multiple surgeries as well as severe knee arthropathy. Complicating matters is a documented cytochrome P450-2C9 defect. To maintain pain control, she required three different opioids with a total daily morphine equivalency dosage of over 2,000mg a day. The stimulants modafinil and phentermine were added to her regimen and she reduced her daily opioid dosage over one-third while claiming about 25 to 30% better pain relief. She has taken stimulants over two years, works full-time, and believes her stimulants are still very effective and indispensable to her pain control regimen.


Case 4. Withdrawal From Opioids


A 43-year-old woman had persistent disabling headaches for 17 years following suspected viral encephalitis. She maintained with three opioids: a daily long-acting morphine, propoxyphene, and hydromorphone. Morphine equivalence was over 1,000mg a day. Phentermine 37.5mg, given 3 times a day, was added to her regimen. She was able to totally cease morphine and propoxyphene within four months.


Summary

The simultaneous use of a stimulant with an opioid should be routinely considered as part of a clinical regimen in those patients who responsibly and reliably take opioids. Benefits include enhanced pain relief, reduction of opioid dosage, cost, and minimization of the side-effects of sedation, fatigue, depression, and mental dullness.

• 1. Melzak R, Mount BM, and Gordon JM. The Brompton mixture versus morphine solution given orally: effects on pain. In: Ajemian I and Mount BM (Eds).The RVH Manual on Palliative/Hospice Care: A Resource Book. Palliative Care Service: Royal Victoria Hospital. Montreal, Quebec, Canada, 1980. p 172.

• 2. Forrest WH Jr, Brown BW Jr, Brown CR, et al. Dextroamphetamine with morphine for the treatment of postoperative pain. N Engl J Med. Mar 1977. 295(13): 712-715.

• 3. Ivy A, Goetzl FR, and Burril DY. Morphine-dextroamphetamine analgesia. War Med. 1944. 6: 67-71.

• 4. DeVoine GJ. The use of Benzedrine sulfate to overcome the untoward effects of morphine in the treatment of coronary occlusion. J Mo Med Assoc. 1941. 38: 93-94.

• 5. Handley CA and Ensberg DL. A comparison of amphetamine sulfate with other stimulants of the central nervous system in morphine respiratory depression. Anesthesiology. 1945. 6: 561-564.

• 6. Ahmed SS, Joglekar GV, and Balwani JH. Potentiation of the analgesic effect of codeine in rates by d-amphetamine. Arch Int Pharmacodyn Ther. Jan 1966. 159(1): 185-188.

• 7. Kulkarni SD, Joglekar GV, and Balwaru JH. Modification of aspirin analgesia by amphetamine. J Exp Med Sci. Jun 1967. 11(1): 14-17.

• 8. Nicak A. The influence of serotonine and amphetamine on analgesic effect of morphine after reserpine premedication in rats and mice. Med Pharmacol Exp Int J Exp Med. 1965. 13(1): 43-48.

• 9. Sasson S, Unterwald EM, and Kornetsky C. Potentiation of morphine analgesia by d-amphetamine. Psychopharmacology (Berl). 1986. 90(2): 163-165.

• 10. Dalal S and Melzack R. Potentiation of opioid analgesia by psychostimulant drugs: a review. J Pain Symptom Manage. 1998. 16(4): 245-253.

• 11. Evans WO. The synergism of autonorine drugs on opiate or opioid-induced analgesia: a discussion of its potential utility. Milit Med. 1962. 127: 1000-1003.

• 12. Evans WO and Bergner DP. A comparison of the analgesic potencies of morphine, pentazocine, and a mixture of methamphetamine and pentazocine in the rat. J New Drugs. 1964. 4(2): 82-85.

• 13. Evans WO. The effect of stimulant drugs on opiate induced analgesia. Arch Biol Med Exp (Santiago). 1967. 4: 144-149. 

• 14. Nott MW. Potentiation of morphine analgesia by cocaine in mice. Eur J Pharmacol. 1968. 5(1): 93-99. 

• 15. Weiss B and Laties V. Enhancement of human performance by caffeine and the amphetamines. Pharmacol Rev. 1962. 14: 1-36.

• 16. Richards RK. A study of the effect of d-amphetamine on the toxicity, analgesic potency and swimming impairment caused by potent analgesics in mice. Arch Int Pharmacodyn Ther. 1975. 216(2): 225-245.

• 17. Jasinski DR and Preston KL. Evaluation of mixtures of morphine and d-amphetamine for subjective and physiological effects. Drug Alcohol Depend. 1986. 17(1): 1-13.

• 18. Evans WO and Smith RP. Some effects of morphine and amphetamine on intellectual functions and mood. Psychopharmacologia (Berl). 1964. 6: 49-56.

• 19. Bruera E, Miller MJ, Macmillan K, et al. Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain. Feb 1992. 48(2): 163-166.

• 20. Abel S, Ball ZB, and Harris SC: The advantages to mother and infant of amphetamine in obstetrical analgesia. Am J Obstet Gynecol. 1951. 62(1): 15-27.

• 21. Miksic S, Shearman GT, and Lal H. Differential enhancement of narcotic discrimination and analgesia by amphetamine and haloperidol: an evidence for distinct mechanisms underlying analgesia and euphoria. Subst Alcohol Actions Misuse. 1980. 1(3): 281-285.

• 22. Drago F, Caccamo G, Continella G, et al. Amphetamine-induced analgesia does not involve brain opioids. Eur J Pharmacol. 1984. 101(3-4): 267-269.

• 23. Izenwasser S and Kornetsky C. Potentiation of morphine analgesia by d-amphetamine is mediated by norepinephrine and not dopamine. Pain. 1988. 33(3): 363-368.