Gabapentinoids in Chronic Pain
Stephanie Nichols, PharmD, BCPS, BCPP, FCCP [email protected] Introducing Penny Lane
Medications
• 53 year old female who presents to your Amlodipine 10mg daily practice after recently moving to Maine Aspirin 81mg daily from Arizona. • PMH: Hypertension, chronic back pain Calcium 500mg and vitamin D 1000 units BID related to a slipped disc, obesity, major Hydrocodone 5mg & acetaminophen 325mg TID depressive disorder, osteoporosis, CAD, alcohol use disorder, and pre-diabetes. Ibuprofen 400mg TID PRN pain • She presents for an early refill of her hydrocodone/acetaminophen and requests Lisinopril 20mg daily a dose increase for ongoing pain. You are Metformin ER 1000mg daily concerned about opioid induced hyperalgesia. Metoprolol XL 100mg daily Sertraline 100mg daily Opioid Induced Hyperalgesia: Patients on sufentanil displayed Control Sufentanil a lower threshold for pain and Sufentanil + withdrew more quickly to pain levobupivacaine stimuli versus controls
Gomez-Brouchet et al. Journal of Translational Medicine 2015;13:208 Opioid Induced Hyperalgesia
• Hyperalgesia (↓ pain tolerance) is important and real • Patients with OUD (+/- pharmacotherapy) have reduced pain tolerance • vs matched peers • vs siblings without OUD • ↓ by gabapentinoids and/or alpha 2 agonists? Ketamine? • With chronic pain, reducing opioid dose can alleviate this
Alford, Ann Intern Med. 2006 Jan 17; 144(2): 127–134. Sirohi, J Pain Res. 2016; 9: 963–966. • Opioids are not the best option for neuropathic pain in general, and there are some signs of opioid induced hyperalgesia in Penny.
• You plan to compassionately taper opioids in Penny and initiate an alternative treatment Non-Opioid Options
• Adjunctive, non-opioid therapy • NSAIDs (oral or IV) or acetaminophen (APAP) (oral or IV) • Ibuprofen 400 mg plus APAP 1,000 mg is equivalent to one oxycodone/APAP 5/325 mg, hydrocodone/APAP 5/325 mg, or APAP/codeine 30/300mg tablet in acute lower extremity pain • Ibuprofen plus APAP is more effective than hydrocodone/APAP 5/325 mg for post-operative dental pain on systemic review • Epidurals and other peripheral nerve blocks • Topics agents: lidocaine patch, NSAID cream, menthol balm, capsaicin cream • Antidepressants (TCAs and SNRIs) • Gabapentinoids (gabapentin and pregabalin)
1. Chang, JAMA. 2017;318(17):1661–1667. 2. Moore, The Journal of the American Dental Association. 2013;144(8):898 – 908. Some Options for Penny
• Non pharmacotherapy: acupuncture, Reiki, massage, PT, etc
• Switch her antidepressant to an SNRI (or TCA) • Risk: worsening depression or intolerable noradrenergic or anticholinergic adverse effects • Schedule NSAID • Risk: worsen hypertension and risk of PUD with heavy alcohol use • Schedule acetaminophen • Risk: hepatotoxicity with heavy alcohol use • Prescribe lidocaine patch • Risk: inefficacy vs high cost • Prescribe gabapentin or pregabalin • Risk: sedation and edema After giving Penny the information, she elects to begin a gabapentinoid Dosing Considerations and Special Populations
Gabapentin (Neurontin) Pregabalin (Lyrica)
• Initial: 100 - 300mg daily to TID • Initial: 25 – 150mg/day (daily or BID) • Titrate up as tolerated • Titrate by 25 – 150mg/d in weekly or • Goal: 300 – 1200mg TID longer intervals • 900 – 3600mg per day • Goal: 300 – 600mg/day • Significantly reduce dose with CrCl • Divided BID to TID < 60ml/min • Max 1400mg/d for 30-59ml/min • Half dose with CrCl < 60ml/min, again when <30ml/min, and again when • No adjustment for hepatic <15ml/min impairment • Use caution in geriatric patients • No adjustment for hepatic impairment but use caution in geriatric patients Medication Formulations
Gabapentin (Neurontin) Pregabalin (Lyrica)
• Capsules • Capsules • 100mg, 300mg, 400mg • 25mg, 50mg, 75mg, 100mg • Tablet • 150mg, 200mg, 225mg, 300mg • 600mg, 800mg • Oral Solution • Oral solution • 20mg/ml • 50mg/ml • 24 hour extended release capsule • Long acting oral tablet (Gralise) (Lyrica CR) 82.5mg, 165mg, 330mg • 300mg, 600mg • Differences Between Pregabalin and Gabapentin
• Both work by binding to the alph-2 delt-1 subunit of the L-type voltage gated calcium channels and modulating release of excitatory neurotransmitters • Presynaptic channels modulate the release of glutamate, norepinephrine, serotonin, dopamine, substance P, and calcitonin gene-related peptide • Both require facilitated transport across cellular membranes through system L- amino acid transporters (Dose-dependent and saturable process) • Gabapentin absorption is localized to the small intestine while pregabalin absorption extends to the ascending colon • Pregabalin is more completely absorbed while the absorption of gabapentin is more variable • Pregabalin bioavailability remains >90% at all therapeutic doses • Food delays absorption but fasting decreases AUC of XR product by 30% • Gabapentin bioavailability = 60% when dosed at 900mg/day and <33% at doses > 3600mg/day • Peak plasma levels of gabapentin occur 3 hours post dose • Rough dose equivalency: 450mg/day pregabalin is similar to 3600mg/day gabapentin Switching between the gabapentinoids
• Dosages were switched using the following algorithm: • Gabapentin ≤900 mg/day → pregabalin 150mg/day • Gabapentin 901 mg/day to 1500 mg/day → pregabalin 225 mg/day • Gabapentin 1501 mg/day 2100 mg/day → pregabalin 300 mg/day • Gabapentin 2101 mg/day 2700 mg/day → pregabalin 450 mg/day • Gabapentin >2700 mg/day → pregabalin 600 mg/day • Gabapentin stopped after the nighttime dose and pregabalin started the following morning • This rapid change was generally well tolerated by patients She expresses a desire to try the cheapest option available.
• Renal function is determined to be normal (CrCl > 60 ml/min)
• Gabapentin is initiated at 100mg TID with a plan to increase to 200mg TID in 7 days and to 300mg TID another 7 days after that. You prescribe 100mg capsules.
• You plan to follow up with Penny in 2 weeks to assess tolerability and effectiveness. At that visit, you plan to either increase the dose to 400mg TID or hold tight at 300mg TID and prescribe the 300mg capsules. You will follow up again with Penny in 3 months. Gabapentinoid Tolerability on Cochrane Review
RR 95% CI Dizziness 1.99 1.94 – 3.37 Fatigue 1.85 1.12 – 3.05 Mentation Difficulties 3.34 1.54 – 7.25 Visual Disturbances 5.72 1.94 – 16.91 Monitoring
• Renal function for dosing • Sedation and somnolence • Dizziness • Ocular disturbance (visual field loss or blurred vision) (pregabalin) • Up to 13% of patients • Suicidal ideation • Myopathy or muscle weakness or pain (pregabalin) • Edema or weight gain (pregabalin) • Up to 16% of patients Penny Lane Returns Medications Amlodipine 10mg daily • 56 year old female who re-presents Aspirin 81mg daily to your practice after visiting her family “back home” for the past Calcium 500mg and vitamin D 1000 units BID several months. Gabapentin 300mg TID • She presents for a refill of all her medications and a yearly check-up. Ibuprofen 400mg TID PRN pain • PMH: Hypertension, chronic back Lisinopril 40mg daily pain, obesity, major depressive Metformin ER 1000mg daily disorder, osteoporosis, CAD s/p MI, alcohol use disorder, and pre- Metoprolol XL 200mg daily diabetes. Pregabalin 100mg TID Sertraline 100mg daily What is your concern with Penny’s medication list?
Medications Amlodipine 10mg daily Aspirin 81mg daily Calcium 500mg and vitamin D 1000 units BID Gabapentin 300mg TID Ibuprofen 400mg TID PRN pain Lisinopril 40mg daily Metformin ER 1000mg daily Metoprolol XL 200mg daily Pregabalin 100mg TID Sertraline 100mg daily • There is no therapeutic indication for multiple gabapentinoids at the same time and they compete for the same transporter for absorption
• Best to pick one agent and optimize it • In Penny, we can stop the gabapentin 300mg TID and replace with another 50mg TID of pregabalin for a new dose of 150mg TID. This switch can be abrupt.
• Educate Penny about gapapentin expectations and pain threshold • Moving the threshold up vs eliminating pain Medications Penny Lane Return Yet Again Amlodipine 10mg daily Aspirin 81mg daily
• 59 year old female who re-presents Calcium 500mg & vitamin D 1000 units BID to your practice after being Furosemide 80mg BID hospitalized with new onset heart failure with reduced ejection Ibuprofen 400mg TID PRN pain fraction (35%). Lisinopril 40mg daily • PMH: Hypertension, chronic back Metformin ER 1000mg daily pain, obesity, major depressive disorder, osteoporosis, CAD s/p MI, Metoprolol XL 200mg daily HF with reduced EF (35%), alcohol Pregabalin 150mg TID use disorder, and pre-diabetes. Sertraline 100mg daily Spironolactone 50mg daily What is your concern with Penny’s medication list at this point?
Medications Amlodipine 10mg daily Aspirin 81mg daily Calcium 500mg & vitamin D 1000 units BID Furosemide 80mg BID Ibuprofen 400mg TID PRN pain Lisinopril 40mg daily Metformin ER 1000mg daily Metoprolol XL 200mg daily Pregabalin 150mg TID Sertraline 100mg daily Spironolactone 50mg daily Pregabalin and Heart Failure
• Edema and cardiac congestion can occur in up to 16% of patients • Peripheral edema followed by central edema • New York Heart Association issued a warning about using caution when prescribing pregabalin to type III-IV heart failure patients • Case reports of pregabalin induced heart failure • Avoid combining with TZDs (eg. pioglitasone) • Risk is also present with gabapentin • 1.2% vs 1.3% risk in a study of nearly 20,000 patients >65 years old
HO JM et al. Pharmacoepidemiol Drug Saf. 2017 Sep;26(9):1087-1092. Penny’s plan
• Taper off pregabalin due to new onset heart failure • Abrupt discontinuation of gabapentin and pregabalin are associated with seizures even in patients without an underlying disorder. • Taper therapy off to avoid precipitating a seizure even when being used for analgesic purposes. • Also d/c PRN ibuprofen due to sodium retention and nephrotoxic risk with loop
• For pain, consider switching Penny’s sertraline to an SNRI such as duloxetine or venlafaxine at doses 150mg/day or higher Take Home Points
• Gabapentinoids are useful for pain and can help reduce the pain threshold • Doses should be tapered up and tapered off • Major differences between gabapentin and pregabalin lie in bioavailability and GI absorption • Most common AEs of pregabalin include sedation, somnolence, dizziness, fatigue, and visual disturbances • Rare but important AEs include: edema and heart failure, suicidal ideation, withdrawal seizures, and myopathy • Patients should be educated that gabapentinoids are one part of a multimodal treatment plan for chronic pain (including non pharmacotherapy) Thank you! Any Questions?