a 60-year - old white female presented to a primary care clinic in february 2011 after opioid detoxification , requesting buprenorphine / naloxone therapy for opioid dependence .
medical history included hypertension , depression , insomnia , headaches , chronic kidney disease ( serum creatinine 1.85 mg / dl ) , and 35 years of abusing various substances , including cocaine , methamphetamine , and , most recently , oxycodone and hydromorphone .
chronic medications included metoprolol 50 mg twice daily and clonidine 0.2 mg twice daily for hypertension and amitriptyline 100 mg at bedtime for depression .
after adding lisinopril 10 mg daily for blood pressure control and appropriate induction onto buprenorphine / naloxone , the patient was stabilized on sublingual buprenorphine / naloxone two 8/2 mg strips per day . in light of the patient 's chronic headache pain and the fact that buprenorphine 's duration of action as an analgesic is relatively short (
6 - 9 hours ) ( center for substance abuse treatment , 2004 ) , the dose was divided and administered twice daily , rather than as a single daily dose , as recommended for patients with opioid dependence alone ( center for substance abuse treatment , 2004 ) .
subsequently , the patient complained of continuing craving and headache pain , and the dose was increased to 8 mg/2 mg 3 times daily . she committed to attend 12-step meetings . at follow - up in april ,
, she was hospitalized for headache , nausea , vomiting , hypertensive urgency ( bp 182/102 mm hg ) , and acute renal insufficiency ( creatinine 1.85 mg / dl ) .
she was managed with clonidine and labetalol and discharged after 36 hours ( bp 153/96 mm hg and creatinine 1.25 mg / dl ) .
the patient 's daughter reported that the patient was experiencing altered mental status with hallucinations ; she suspected ongoing medication abuse .
the patient was taken to a detoxification unit but left against medical advice . owing to suspicion of possible relapse to prescription drug abuse ,
the primary care staff called 4 local pharmacies and confirmed that she had received 690 tablets of clonidine 0.2 mg within 33 days .
after requests for further clonidine refills were refused , patient returned to the office june 27 , where she refused inpatient treatment , agreed to stop using clonidine , and received prescriptions for diltiazem , lisinopril , hydrochlorothiazide , and buprenorphine / naloxone . in july ,
the daughter called reporting the patient , who lived alone , had been evaluated at a local emergency department after taking high doses of  some medication ,  passing out , and hitting her head .
the primary care team again contacted local pharmacies and found that , in addition to her buprenorphine / naloxone , she had obtained 810 tablets of clonidine 0.2 mg and 180 tablets of amitriptyline 100 mg over the previous 7 weeks , all using prescriptions from the primary care office .
she returned to the office in august , presenting with severe headache , hypertensive urgency ( bp 174/109 mm hg ) , and acute renal insufficiency ( creatinine 2.08 ) .
urine drug screen was negative for opioids or other illicit drugs ( buprenorphine testing was not performed ) . during psychiatric evaluation
, she admitted that she was  addicted to clonidine ,  claiming it was the only drug that controlled her bp and denying that it gave her a high . at no point
magnetic resonance imaging showed cerebral and cerebellar atrophy , areas of encephalomalacia , and lacunar infarcts .
she again refused substance abuse inpatient treatment and was discharged on metoprolol , lisinopril / hydrochlorothiazide , and buprenorphine / naloxone .
increased buprenorphine prescribing and rising numbers of buprenorphine - related emergency department visits highlight the need for practitioners to recognize the potential for use of buprenorphine / naloxone in combination with other drugs to achieve a mood - altering state .
high levels of concomitant abuse of clonidine and opioids , particularly methadone , have been reported in some us regions ( beuger et al . , 1998 ; dennison , 2001 ) . when combined with review of her pharmacy records ,
this patient 's recurrent bouts of rebound hypertension and renal insufficiency suggest abuse of clonidine ( followed by abrupt discontinuation ) during buprenorphine maintenance , whereas periodic hallucinations suggest concomitant amitriptyline abuse as well ( prahlow and landrum , 2005 ) .
her fall may have been caused by hypotension , which can result from taking high doses of clonidine , or dizziness , a reported side effect of buprenorphine ( center for substance abuse treatment , 2004 ) .
all available evidence suggests that she was taking buprenorphine / naloxone as prescribed , although the dose administered is at the upper end of current prescribing guidelines and has been associated with some untoward effects , including diversion ( walsh , 2011 ) .
although evidence for abuse of buprenorphine / naloxone is not clear , the patient seems to have combined several pharmaceuticals with mood - altering properties to create a kind of  medication cocktail ,  which resulted in recurrent impairment .
an online review of conversations from drug forums and pharmacist blogs in july 2013 found numerous references to individuals seeking  highs  by combining buprenorphine / naloxone with clonidine or gabapentin .
clonidine , amitriptyline , and gabapentin are all commonly prescribed medications in primary care , where most buprenorphine / naloxone is prescribed .
many primary care providers may not be aware of their abuse potential . unlike alcohol and benzodiazepines , which may also be combined with buprenorphine to achieve a mood - altering state , these medications
this patient 's declining renal function and abnormal magnetic resonance imaging point to the potentially serious complications of uncontrolled and rebound hypertension , which are frequent in patients who abuse clonidine .
what is the prevalence of concomitant use of these medications in patients on buprenorphine maintenance and what are their effects on treatment outcomes ?
the metabolic pathways of these medications also suggest 1 or more possible mechanisms for the observed interaction that warrant further exploration .
both buprenorphine and clonidine are metabolized by cyp450 - 3a4 and 3a5 systems ( claessens et al . , 2010 ;
buprenorphine and amitriptyline are metabolized by cyp450 - 2c9 system ( olesen and linnet , 1997 ) , and amitriptyline and clonidine are metabolized by cyp450 - 2d6 system ( olesen and linnet , 1997 ) .
could 1 or more of these interactions increase serum levels or prolong the half - life of some of the medications involved ?
if so , what is the impact on creation or enhancement of a mood - altering state ?
pharmacists and physicians should be aware of the potential for abuse of clonidine , amitriptyline , and possibly gabapentin in patients on buprenorphine maintenance and should seek to avoid using these medications in combination with buprenorphine whenever possible .
consideration should also be given to including this information in packaging information for buprenorphine products and in buprenorphine education programs such as providers ' clinical support system for medication assisted treatment , an excellent source of up - to - date information on buprenorphine therapy ( pcssmat , 2014 ) .
if these medications are used in combination , special instructions should be included to prevent early or repeated refills , and communication among all medical providers and pharmacists is essential .
patients who use these substances concomitantly to achieve a mood - altering effect should be referred for more intensive substance abuse treatment rather than office - based buprenorphine .
 buprenorphine / naloxone maintenance therapy is often prescribed in primary care to treat opioid dependence . 
 previous reports have described concomitant abuse of opioids and clonidine . in this case , a primary care patient on buprenorphine / naloxone maintenance therapy demonstrating altered mental status , hallucinations , falls , and rebound hypertension was found to be concomitantly abusing clonidine and amitryptyline , which share metabolic pathways with buprenorphine . 
 clinicians should be aware of patients ' combining amitryptyline , clonidine , and gabapentin with buprenorphine to achieve a mood altering state , avoid co - prescribing them if possible , and maintain communication with pharmacies and other providers when they are prescribed . 
CASE REPORT
DISCUSSION