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## Opioid Use Disorder (OUD) — QSP / PK-PD Model

## ============================================================================

## Disease : OUD — mu-opioid receptor (MOR) agonism drives acute reward/

## analgesia, chronic neuroadaptation (tolerance, opponent-process

## withdrawal via locus-coeruleus noradrenergic rebound), and

## dose-dependent respiratory depression/overdose risk. Model

## tracks receptor occupancy from competing ligands (illicit

## fentanyl, methadone, buprenorphine, naloxone, naltrexone) and

## downstream withdrawal, craving, respiratory, and cardiac

## (methadone QTc) endpoints.

## Authors : Generated by Claude Code Routine (QSP Disease Model Library)

## Engine : mrgsolve (>=1.5)

## Scope : 23 ODE compartments — drug PK (illicit fentanyl 3 [gut+central+

## peripheral], methadone 2, buprenorphine 3 [SL depot+XR depot+

## central], naloxone 2, naltrexone 3 [oral+XR depot+central],

## lofexidine 2 = 15) + disease/PD network (MOR tolerance,

## locus-coeruleus/noradrenergic tone, withdrawal COWS, craving

## VAS, respiratory-drive index, methadone QTc, phasic dopamine/

## euphoria, treatment-retention index = 8).

## Time : hours (acute PK/overdose minutes-hours; tolerance/withdrawal

## hours-days; treatment retention weeks). Default horizon

## 0-672 h (4 weeks); acute-overdose scenarios use 0-6 h.

## Units : dose mg; concentration mg/L (ng/mL numerically equal x1000

## scale handled via V); MOR occupancy fraction 0-1; COWS 0-48

## (clinical scale, rescaled 0-100 internally then reported 0-48);

## craving VAS 0-100; QTc ms; dopamine/euphoria index 0-100;

## respiratory index 1.0 = normal minute ventilation, 0 = apnea.

## Scenarios: 10 prebuilt — see OUD_simulate_scenarios() at bottom.

## Anchors : Volkow 2016 NEJM (neurobiology of addiction, mesolimbic/LC

## opponent-process model); Koob & Volkow 2016 Lancet Psychiatry

## (anti-reward/dynorphin-KOR system); Wesson & Ling 2003 J

## Psychoactive Drugs (COWS scale); Dahan 2010 Br J Anaesth /

## Dahan 2005 Anesthesiology (opioid-induced respiratory

## depression, competitive-antagonism PK/PD & buprenorphine

## ceiling); Walsh 1994 Clin Pharmacol Ther / Greenwald 2003

## Neuropsychopharmacology (buprenorphine MOR occupancy PET,

## ceiling on subjective/physiologic effects); Comer 2005 Am J

## Psychiatry (naltrexone XR blockade duration); Krupitsky 2011

## Lancet (naltrexone XR RCT); Kampman & Jarvis 2015 ASAM

## National Practice Guideline (dosing anchors); Chou 2014 Ann

## Intern Med (methadone QTc / torsades risk review); Krantz 2009

## Ann Intern Med (methadone-associated QT prolongation); Gowing

## 2016 Cochrane (lofexidine/alpha2-agonist withdrawal

## management); Mattick 2014 Cochrane (buprenorphine/methadone

## maintenance treatment retention); Sordo 2017 BMJ (mortality

## risk reduction with agonist maintenance treatment).

## Disclaimer: For research / education / hypothesis generation only. Not a

## substitute for clinical judgment, addiction-medicine practice

## guidelines, or regulatory decision-making.

## ============================================================================

[PROB]

QSP model of opioid use disorder (OUD) linking competitive mu-opioid-receptor

(MOR) occupancy from illicit fentanyl, methadone, buprenorphine, naloxone, and

naltrexone to chronic-tolerance/withdrawal neuroadaptation (locus-coeruleus

noradrenergic rebound), craving/relapse risk, dose-dependent respiratory

depression/overdose, methadone-associated QTc prolongation, and treatment-

retention outcomes, with symptomatic alpha2-agonist (lofexidine) withdrawal

management.

[PLUGIN] Rcpp

[PARAM] @annotated

//--- Patient / history

AGE : 34 : age (years)

WT : 72 : body weight (kg)

YEARS_USE : 5 : years of regular opioid use (chronic-exposure driver)

BASE_TOL : 0.55 : baseline MOR tolerance/adaptation index (0=naive,1=max)

BASE_COWS : 2 : baseline (inter-dose) COWS withdrawal score (0-48)

BASE_CRAVE : 30 : baseline craving VAS (0-100)

BASE_RETAIN : 0.20 : baseline treatment-retention index (0-1)

BENZO_COUSE : 0 : 1 = concurrent benzodiazepine/sedative co-use (synergistic resp. depression)

XYLAZINE_ADULT : 0 : 1 = illicit supply adulterated with xylazine (naloxone-refractory sedation component)

COUNSELING : 0 : 1 = structured counseling/contingency-management engaged

//--- Illicit fentanyl/heroin PK (surrogate "fentanyl-equivalent"; IV/IN/smoked;

// highly lipophilic, rapid central-peripheral redistribution; central t1/2~20 min,

// context-sensitive terminal t1/2 lengthens with repeated dosing)

CL_FENT : 55 : L/h (hepatic, high extraction)

V1_FENT : 25 : L (central)

V2_FENT : 175 : L (peripheral, lipophilic)

Q_FENT : 45 : L/h (inter-compartmental)

KA_FENT_IN : 6.0 : 1/h (intranasal/smoked absorption; IV = direct bolus into V1)

F_FENT_IN : 0.70

//--- Methadone PK (oral; long, variable t1/2 8-59h; CYP3A4/CYP2B6)

KA_METH : 0.9

F_METH : 0.85

CL_METH : 5.0 : L/h (low, variable clearance drives long t1/2)

V_METH : 300 : L (large Vd)

//--- Buprenorphine PK (sublingual film/tablet or SC depot; high affinity, long

// receptor residence; SL F~0.30; depot near-zero-order release ~1 month)

KA_BUP_SL : 1.2

F_BUP_SL : 0.30

CL_BUP : 80 : L/h

V_BUP : 300 : L

KREL_BUP_XR : 0.0014 : 1/h (depot zero-order-like slow release, ~monthly duration)

//--- Naloxone PK (IN/IM/auto-injector; short t1/2 ~30-90 min)

KA_NLX : 3.5

F_NLX_IN : 0.50

CL_NLX : 120 : L/h

V_NLX : 200 : L

//--- Naltrexone PK (oral daily 50 mg; XR-IM depot 380 mg/month, Vivitrol-type

// near-zero-order release with initial burst)

KA_NTX_PO : 1.5

F_NTX_PO : 0.90

CL_NTX : 150 : L/h

V_NTX : 500 : L

KREL_NTX_XR : 0.0018 : 1/h (slow depot release, ~monthly duration)

//--- Lofexidine PK (oral alpha2-agonist; t1/2 ~12-16h)

KA_LOF : 0.8

F_LOF : 0.72

CL_LOF : 15 : L/h

V_LOF : 240 : L

//--- MOR occupancy (algebraic, competitive Emax across agonists/antagonists;

// relative affinity constants, Ki in ng/mL-equivalent units — buprenorphine

// highest affinity, naloxone/naltrexone high affinity but zero intrinsic

// activity, fentanyl/methadone high efficacy full agonists)

KI_FENT : 1.0 : ng/mL-equiv affinity constant (reference)

KI_METH : 25 : ng/mL-equiv (lower potency than fentanyl by mass)

KI_BUP : 0.20 : ng/mL-equiv (very high affinity)

KI_NLX : 1.0 : ng/mL-equiv (high affinity, zero efficacy)

KI_NTX : 0.80 : ng/mL-equiv (high affinity, zero efficacy)

EFF_FENT : 1.00 : intrinsic efficacy (full agonist)

EFF_METH : 1.00 : intrinsic efficacy (full agonist)

EFF_BUP : 0.45 : intrinsic efficacy (partial agonist, ceiling)

//--- Tolerance / receptor adaptation turnover (days-scale)

KOUT_TOL : 0.006 : 1/h

TOL_DRIVE_GAIN: 0.9 : max tolerance driven by sustained high MOR occupancy

//--- Locus-coeruleus noradrenergic tone / withdrawal drive turnover

KOUT_LC : 0.35 : 1/h (fast, reflects acute occupancy-drop rebound)

LC_REBOUND_GAIN: 3.2 : LC-tone gain per unit (tolerance x occupancy-deficit)

EC50_LOF_LC : 0.008 : mg/L, lofexidine EC50 for LC noradrenergic suppression

EMAX_LOF_LC : 0.70 : max fractional LC-tone suppression from lofexidine

//--- Withdrawal (COWS surrogate, 0-48) turnover

KOUT_COWS : 0.45 : 1/h (fast, tracks LC tone closely)

SCALE_COWS_LC : 46 : COWS points per unit LC-tone excess above 1.0

//--- Craving (VAS 0-100) turnover

KOUT_CRAVE : 0.020 : 1/h (slower, days-scale)

SCALE_CRAVE_COWS : 0.9 : craving points per COWS point

SCALE_CRAVE_TOL : 25 : craving points per unit tolerance

COUNSELING_CRAVE_RED : 0.35 : fractional craving reduction from counseling/contingency management

//--- Respiratory drive index (1.0 normal, fast turnover minutes)

KOUT_RESP : 2.0 : 1/h

RESP_EMAX_MOR : 0.97 : max fractional respiratory-drive suppression at full agonist saturation

RESP_GAMMA : 1.6 : Hill coefficient (steep dose-response near overdose threshold)

BUP_CEILING_OCC : 0.55 : occupancy ceiling above which buprenorphine's partial-agonist effect plateaus

BENZO_RESP_MULT : 1.6 : multiplicative respiratory-suppression synergy factor if BENZO_COUSE=1

XYLAZINE_RESP_ADD : 0.15 : additive respiratory-suppression from xylazine (naloxone-refractory)

RESP_APNEA_THRESHOLD : 0.25 : respiratory index below which apnea/overdose flagged

//--- Methadone-associated QTc (ms) turnover (slow, accumulation-linked)

KOUT_QTC : 0.01 : 1/h

QTC_BASE : 420 : ms

EC50_METH_QTC : 0.30 : mg/L, methadone EC50 for hERG-linked QTc prolongation

EMAX_METH_QTC : 65 : ms, max QTc prolongation from methadone

//--- Phasic dopamine / euphoria index (0-100, fast turnover)

KOUT_DA : 1.2 : 1/h

DA_GAIN_NEWOCC: 140 : dopamine points per unit of *newly acquired* MOR occupancy (delta, blunted by tolerance)

//--- Treatment-retention index (0-1, slow weeks-scale)

KOUT_RETAIN : 0.004 : 1/h

RETAIN_TARGET_BASE : 0.25

RETAIN_MAT_BONUS : 0.55 : retention bonus from being on agonist/antagonist maintenance (occupancy-stabilized)

RETAIN_COWS_PENALTY: 0.02 : retention loss per COWS point

RETAIN_COUNSEL_BONUS: 0.20 : retention bonus from counseling engagement

[CMT] @annotated

GUT_FENT : Illicit fentanyl IN/smoked depot (mg)

CEN_FENT : Fentanyl central plasma (mg)

PER_FENT : Fentanyl peripheral/tissue (mg)

GUT_METH : Methadone gut depot (mg)

CEN_METH : Methadone plasma (mg)

GUT_BUP : Buprenorphine SL depot (mg)

DEPOT_BUP_XR : Buprenorphine XR-SC depot (mg)

CEN_BUP : Buprenorphine plasma (mg)

GUT_NLX : Naloxone IN/IM depot (mg)

CEN_NLX : Naloxone plasma (mg)

GUT_NTX : Naltrexone oral depot (mg)

DEPOT_NTX_XR : Naltrexone XR-IM depot (mg)

CEN_NTX : Naltrexone plasma (mg)

GUT_LOF : Lofexidine gut depot (mg)

CEN_LOF : Lofexidine plasma (mg)

TOL : MOR tolerance/adaptation index (0-1)

LC : Relative locus-coeruleus noradrenergic tone (1.0=normal)

COWS : Clinical Opiate Withdrawal Scale composite (0-48)

CRAVE : Craving VAS (0-100)

RESP : Relative respiratory-drive index (1.0=normal, 0=apnea)

QTC : Methadone-associated QTc interval (ms)

DA : Phasic dopamine/euphoria index (0-100)

RETAIN : Treatment-retention index (0-1)

[MAIN]

GUT_FENT_0 = 0; CEN_FENT_0 = 0; PER_FENT_0 = 0;

GUT_METH_0 = 0; CEN_METH_0 = 0;

GUT_BUP_0 = 0; DEPOT_BUP_XR_0 = 0; CEN_BUP_0 = 0;

GUT_NLX_0 = 0; CEN_NLX_0 = 0;

GUT_NTX_0 = 0; DEPOT_NTX_XR_0 = 0; CEN_NTX_0 = 0;

GUT_LOF_0 = 0; CEN_LOF_0 = 0;

TOL_0 = BASE_TOL;

LC_0 = 1.0 + (BASE_COWS/SCALE_COWS_LC);

COWS_0 = BASE_COWS;

CRAVE_0 = BASE_CRAVE;

RESP_0 = 1.0;

QTC_0 = QTC_BASE;

DA_0 = 0;

RETAIN_0 = BASE_RETAIN;

[ODE]

// ---------- PK ----------

double CFENT1 = CEN_FENT / V1_FENT;

double CFENT2 = PER_FENT / V2_FENT;

double CMETH = CEN_METH / V_METH;

double CBUP = CEN_BUP / V_BUP;

double CNLX = CEN_NLX / V_NLX;

double CNTX = CEN_NTX / V_NTX;

double CLOF = CEN_LOF / V_LOF;

dxdt_GUT_FENT = -KA_FENT_IN * GUT_FENT;

dxdt_CEN_FENT = F_FENT_IN * KA_FENT_IN * GUT_FENT

- (CL_FENT/V1_FENT) * CEN_FENT

- (Q_FENT/V1_FENT) * CEN_FENT + (Q_FENT/V2_FENT) * PER_FENT;

dxdt_PER_FENT = (Q_FENT/V1_FENT) * CEN_FENT - (Q_FENT/V2_FENT) * PER_FENT;

dxdt_GUT_METH = -KA_METH * GUT_METH;

dxdt_CEN_METH = F_METH * KA_METH * GUT_METH - (CL_METH/V_METH) * CEN_METH;

dxdt_GUT_BUP = -KA_BUP_SL * GUT_BUP;

dxdt_DEPOT_BUP_XR = -KREL_BUP_XR * DEPOT_BUP_XR;

dxdt_CEN_BUP = F_BUP_SL * KA_BUP_SL * GUT_BUP + KREL_BUP_XR * DEPOT_BUP_XR

- (CL_BUP/V_BUP) * CEN_BUP;

dxdt_GUT_NLX = -KA_NLX * GUT_NLX;

dxdt_CEN_NLX = F_NLX_IN * KA_NLX * GUT_NLX - (CL_NLX/V_NLX) * CEN_NLX;

dxdt_GUT_NTX = -KA_NTX_PO * GUT_NTX;

dxdt_DEPOT_NTX_XR = -KREL_NTX_XR * DEPOT_NTX_XR;

dxdt_CEN_NTX = F_NTX_PO * KA_NTX_PO * GUT_NTX + KREL_NTX_XR * DEPOT_NTX_XR

- (CL_NTX/V_NTX) * CEN_NTX;

dxdt_GUT_LOF = -KA_LOF * GUT_LOF;

dxdt_CEN_LOF = F_LOF * KA_LOF * GUT_LOF - (CL_LOF/V_LOF) * CEN_LOF;

// ---------- MOR occupancy: competitive-antagonism / multi-ligand Emax ----------

// Convert plasma "mg/L" to ng/mL-equivalent (numerically identical) for Ki comparison.

double a_fent = CFENT1 / KI_FENT;

double a_meth = CMETH / KI_METH;

double a_bup = CBUP / KI_BUP;

double a_nlx = CNLX / KI_NLX;

double a_ntx = CNTX / KI_NTX;

double sum_a = a_fent + a_meth + a_bup + a_nlx + a_ntx;

double occ_total = sum_a / (1.0 + sum_a); // total fractional MOR occupancy (all ligands)

double occ_agonist_frac = (sum_a > 1e-9) ? (a_fent + a_meth + a_bup) / sum_a : 0.0;

// Effective agonist-weighted occupancy (partial agonist ceiling applied to buprenorphine share)

double occ_full = (sum_a > 1e-9) ? occ_total * ((a_fent*EFF_FENT + a_meth*EFF_METH + a_bup*EFF_BUP) / sum_a) : 0.0;

double occ_eff = occ_full;

if (occ_eff > BUP_CEILING_OCC && (a_bup > a_fent) && (a_bup > a_meth)) {

// buprenorphine-dominated regime: enforce partial-agonist ceiling

occ_eff = BUP_CEILING_OCC + (occ_eff - BUP_CEILING_OCC) * 0.15;

}

// ---------- Tolerance/adaptation (slow; driven by sustained effective occupancy) ----------

double TOL_target = TOL_DRIVE_GAIN * occ_eff + BASE_TOL * (1.0 - occ_eff*0.3);

if (TOL_target > 1.0) TOL_target = 1.0;

dxdt_TOL = KOUT_TOL * (TOL_target - TOL);

// ---------- Locus-coeruleus tone (opponent-process rebound on occupancy deficit) ----------

double occ_deficit = TOL - occ_eff; // positive when tolerance exceeds current occupancy (withdrawal state)

if (occ_deficit < 0) occ_deficit = 0;

double lof_fx = EMAX_LOF_LC * CLOF / (EC50_LOF_LC + CLOF);

double LC_target = 1.0 + LC_REBOUND_GAIN * occ_deficit * (1.0 - lof_fx);

dxdt_LC = KOUT_LC * (LC_target - LC);

// ---------- Withdrawal (COWS) ----------

double lc_excess = LC - 1.0;

if (lc_excess < 0) lc_excess = 0;

double COWS_target = SCALE_COWS_LC * lc_excess;

if (COWS_target > 48) COWS_target = 48;

dxdt_COWS = KOUT_COWS * (COWS_target - COWS);

// ---------- Craving ----------

double counsel_fx = (COUNSELING > 0) ? (1.0 - COUNSELING_CRAVE_RED) : 1.0;

double CRAVE_target = (SCALE_CRAVE_COWS * COWS + SCALE_CRAVE_TOL * TOL) * counsel_fx;

if (CRAVE_target > 100) CRAVE_target = 100;

if (CRAVE_target < 0) CRAVE_target = 0;

dxdt_CRAVE = KOUT_CRAVE * (CRAVE_target - CRAVE);

// ---------- Respiratory drive (Hill suppression by full-agonist occupancy; synergy/adulterant terms) ----------

double occ_h = pow(occ_eff, RESP_GAMMA);

double resp_supp = RESP_EMAX_MOR * occ_h / (pow(0.5, RESP_GAMMA) + occ_h);

double benzo_fx = (BENZO_COUSE > 0) ? BENZO_RESP_MULT : 1.0;

double xyl_fx = (XYLAZINE_ADULT > 0) ? XYLAZINE_RESP_ADD : 0.0;

double RESP_target = 1.0 - resp_supp*benzo_fx - xyl_fx;

if (RESP_target < 0) RESP_target = 0;

dxdt_RESP = KOUT_RESP * (RESP_target - RESP);

// ---------- Methadone QTc ----------

double meth_qtc_fx = EMAX_METH_QTC * CMETH / (EC50_METH_QTC + CMETH);

double QTC_target = QTC_BASE + meth_qtc_fx;

dxdt_QTC = KOUT_QTC * (QTC_target - QTC);

// ---------- Phasic dopamine / euphoria (driven by newly acquired occupancy, blunted by tolerance) ----------

double new_occ = occ_eff - TOL;

if (new_occ < 0) new_occ = 0;

double DA_target = DA_GAIN_NEWOCC * new_occ * (1.0 - 0.6*TOL);

if (DA_target > 100) DA_target = 100;

dxdt_DA = KOUT_DA * (DA_target - DA);

// ---------- Treatment retention ----------

int on_maintenance = (a_bup > 0.05 || CMETH > (5.0/V_METH) || CNTX > (1.0/V_NTX)) ? 1 : 0;

double counsel_bonus = (COUNSELING > 0) ? RETAIN_COUNSEL_BONUS : 0.0;

double RETAIN_target = RETAIN_TARGET_BASE + (on_maintenance ? RETAIN_MAT_BONUS : 0.0)

- RETAIN_COWS_PENALTY*COWS + counsel_bonus;

if (RETAIN_target > 1.0) RETAIN_target = 1.0;

if (RETAIN_target < 0) RETAIN_target = 0;

dxdt_RETAIN = KOUT_RETAIN * (RETAIN_target - RETAIN);

[TABLE]

capture conc_fentanyl = CEN_FENT / V1_FENT;

capture conc_methadone = CEN_METH / V_METH;

capture conc_buprenorphine = CEN_BUP / V_BUP;

capture conc_naloxone = CEN_NLX / V_NLX;

capture conc_naltrexone = CEN_NTX / V_NTX;

capture conc_lofexidine = CEN_LOF / V_LOF;

capture MOR_occupancy_total = ( (CEN_FENT/V1_FENT)/KI_FENT + (CEN_METH/V_METH)/KI_METH + (CEN_BUP/V_BUP)/KI_BUP + (CEN_NLX/V_NLX)/KI_NLX + (CEN_NTX/V_NTX)/KI_NTX ) / (1.0 + (CEN_FENT/V1_FENT)/KI_FENT + (CEN_METH/V_METH)/KI_METH + (CEN_BUP/V_BUP)/KI_BUP + (CEN_NLX/V_NLX)/KI_NLX + (CEN_NTX/V_NTX)/KI_NTX );

capture Tolerance_idx = TOL;

capture LC_tone_idx = LC;

capture COWS_score = COWS;

capture Craving_VAS = CRAVE;

capture Respiratory_idx = RESP;

capture Overdose_flag = (RESP < RESP_APNEA_THRESHOLD) ? 1 : 0;

capture QTc_ms = QTC;

capture Dopamine_idx = DA;

capture Retention_idx = RETAIN;

[CAPTURE]

conc_fentanyl conc_methadone conc_buprenorphine conc_naloxone conc_naltrexone

conc_lofexidine MOR_occupancy_total Tolerance_idx LC_tone_idx COWS_score

Craving_VAS Respiratory_idx Overdose_flag QTc_ms Dopamine_idx Retention_idx

## ============================================================================

## R-side scenario helpers (parsed by users, not by mrgsolve)

## ============================================================================

## library(mrgsolve); library(dplyr); library(tidyr); library(ggplot2)

## mod <- mread_cache("oud_mrgsolve_model.R")

## # ---------- 10 prebuilt scenarios (end_h = simulation horizon, hours) ----------

## OUD_simulate_scenarios <- function(end_h = 672) {

## sc <- list(

## "1. Untreated chronic illicit fentanyl use (IN, q4-6h)" =

## ev(amt=1.5, cmt="GUT_FENT", ii=5, addl=ceiling(end_h/5)),

## "2. Fentanyl overdose (IV bolus) + naloxone rescue at 5 min" =

## seq(ev(amt=3.0, cmt="CEN_FENT", time=0),

## ev(amt=4.0, cmt="GUT_NLX", time=5/60)),

## "3. Methadone maintenance treatment (100 mg PO QD, steady state)" =

## ev(amt=100, cmt="GUT_METH", ii=24, addl=ceiling(end_h/24)),

## "4. Buprenorphine/naloxone SL maintenance (16 mg PO QD)" =

## ev(amt=16, cmt="GUT_BUP", ii=24, addl=ceiling(end_h/24)),

## "5. Precipitated withdrawal: buprenorphine induced too early" =

## seq(ev(amt=1.5, cmt="GUT_FENT", ii=5, addl=6),

## ev(amt=8, cmt="GUT_BUP", time=2)), # induced 2h after last use, high residual occupancy

## "6. Naltrexone XR-IM depot (380 mg, post-detox relapse prevention)" =

## ev(amt=380, cmt="DEPOT_NTX_XR", time=0),

## "7. Untreated abrupt cessation (\"cold turkey\") + lofexidine" =

## ev(amt=0.6, cmt="GUT_LOF", ii=8, addl=3*ceiling(end_h/24)), # after chronic-use history via BASE_TOL

## "8. Illicit fentanyl + benzodiazepine co-use (synergistic depression)" =

## ev(amt=1.5, cmt="GUT_FENT", ii=5, addl=ceiling(end_h/5)), # + BENZO_COUSE=1

## "9. High-dose methadone (140 mg QD) with QTc-risk comorbidity" =

## ev(amt=140, cmt="GUT_METH", ii=24, addl=ceiling(end_h/24)),

## "10. Relapse after buprenorphine discontinuation (tolerance lost)" =

## seq(ev(amt=16, cmt="GUT_BUP", ii=24, addl=30),

## ev(amt=1.5, cmt="GUT_FENT", time=35*24)) # return-to-use after 5-day taper gap

## )

## purrr::imap_dfr(sc, function(e, lab) {

## mod %>% mrgsim(e, end=end_h, delta=0.1) %>%

## as_tibble() %>% mutate(scenario=lab)

## })

## }

## # ---------- Calibration anchors ----------

## # MOR occupancy / respiratory Hill relationship (Dahan 2005/2010): steep,

## # near-threshold suppression of hypoxic ventilatory response at high

## # full-agonist occupancy; buprenorphine plateaus ~40-50% max suppression

## # even at supratherapeutic doses (Walsh 1994; Greenwald 2003 PET occupancy)

## # Naloxone renarcotization (t1/2 30-90 min vs fentanyl/methadone t1/2 hours):

## # repeat dosing/infusion required, esp. for long-acting agonist overdose

## # Methadone QTc (Krantz 2009; Chou 2014 ASAM/ACP guideline): dose-dependent

## # hERG block, torsades risk rises sharply >120-150 mg/day or with

## # hypokalemia/other QT-prolonging drugs

## # Naltrexone XR blockade duration (Comer 2005; Krupitsky 2011 Lancet):

## # near-complete MOR blockade sustained ~28 days per depot injection;

## # overdose risk markedly increases if a lapse in blockade coincides with

## # reduced tolerance and return to prior illicit dosing

## # Maintenance treatment retention & mortality (Mattick 2014 Cochrane; Sordo

## # 2017 BMJ): agonist/partial-agonist maintenance approximately halves

## # all-cause and overdose mortality vs no opioid-agonist treatment

## # COWS/LC-noradrenergic rebound kinetics (Wesson & Ling 2003; Volkow 2016

## # NEJM opponent-process model): peak withdrawal ~36-72h post-short-acting

## # opioid cessation, later/blunted with long-acting agents (methadone)

## # ---------- Quick sanity plots ----------

## # df <- OUD_simulate_scenarios(672)

## # ggplot(df, aes(time, MOR_occupancy_total, colour=scenario)) + geom_line() + xlab("hour")

## # ggplot(df, aes(time, Respiratory_idx, colour=scenario)) + geom_line() +

## # geom_hline(yintercept=0.25, lty=2) + xlab("hour")

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